Carbapenem

ABSTRACT

A compound of the formula ##STR1## in which: R 1&#39;  is hydrogen or a carboxy-protecting group; 
     R 41&#39;  is hydrogen or a hydroxy-protecting group; 
     R 42&#39;  is a C 1  -C 6  alkyl, a C 1  -C 6  alkoxy, a halogen, an aryl or an aryloxy; R 43&#39;  is hydrogen, a C 1  -C 6  alkyl, a C 1  -C 6  alkoxy, a hydroxy, a halogen, a cyano, a nitro or a group of the formula --NR 8&#39;  R 9&#39; , where R 8&#39;  and R 9&#39;  are independently selected from the group consisting of hydrogen, amino-protecting groups, C 1  -C 6  alkyl groups and phenyl groups, or R 8&#39;  and R 9&#39;  together represent a group --(CH 2 ) q  &#39;--O r  &#39;--(CH 2 ) s  &#39;--, where q&#39; and s&#39; are independently 0 or an integer of from 1 to 5 and r&#39; is 0 or 1, provided that (q&#39;+s&#39;) is an integer of at least 2; R 45&#39;  and R 46&#39;  are independently selected from the group consisting of C 1  -C 6  alkyl groups and aryl groups, or R 45&#39;  and R 46&#39;  together represent a group --(CH 2 ) q  &#39;--O r  &#39;--(CH 2 ) s  &#39;--, where q&#39; and s&#39; are independently 0 or an integer of from 1 to 5 and r&#39; is 0 or 1; Y&#39; is oxygen or sulfur; and j&#39; is 0, 1 or 2.

This is a division of application Ser. No. 08/289,133 filed Aug. 11,1994, now U.S. Pat. No. 5,541,317, which is a CIP of both (i)application Ser. No. 08/090,489 filed Jul. 12, 1993 abandoned which is acontinuation of application Ser. No. 07/888,879 filed May 26, 1992(abandoned) and (ii) application Ser. No. 08/119,008 filed Sep. 9, 1993abandoned.

BACKGROUND TO THE INVENTION

The present invention relates to a series of new azetidinone derivativeswhich may be used as intermediates in the preparation of certaincarbapenem antibiotics.

The present invention also relates to a new process for preparing aseries of carbapenem and penem compounds which are useful asantibiotics. The invention also provides a series of novel intermediatesused in this process.

The penam and cephem antibiotics have been known for many years and haveproved of considerable value in the control and prevention of infectiousdiseases. More recently, penem and carbapenem antibiotics have beendeveloped and have also been found to be of great benefit. The penem andcarbapenem compounds have in common a basic structure which may berepresented by the formula (A'): ##STR2## in which Z' represents asulfur atom or a group of formula >CH₂, which may optionally besubstituted by an alkyl or alkoxy group. Those compounds in which Z'represents a sulfur atom are the penem compounds, whilst those in whichZ' represents a group of formula >CH₂ or substituted group of formula>CH₂ are the carbapenem compounds. In accordance with therecommendations of the International Union of Pure and Applied Chemistry(IUPAC), the compounds referred to herein are named semi-systematicallyusing penem and carbapenem as the parent compound. For the avoidance ofdoubt, the above formula (A') also shows the relevant numbers in theperipheral numbering system employed to describe the compounds herein.

Those carbapenem antibiotics having no substituent at the I-position arepotentially a very useful series of compounds which have extraordinarilypotent antibacterial activity. Unfortunately, however, they arechemically unstable and, moreover, are sensitive to dehydropeptidase Iin vivo. Dehydropeptidase I is an enzyme which hydrolyses the β-lactamring in carbapenem antibiotics and which exists in mammalian tissue, forexample in the renal cortex. It is responsible for the extensivemetabolisation of many otherwise valuable β-lactam antibiotics inanimals, including humans, thus greatly reducing their value. Despitethese disadvantages, these carbapenem antibiotics are finding increasinguse in the treatment of bacterial infections. On the other hand, thosecarbapenem antibiotics having a 1β-substituent are chemically stable andare resistant to the dehydropeptidase I enzyme. However, none of thisseries of compounds has been found in nature, and the compounds must,accordingly, be prepared by chemical synthesis. As with manybiologically active compounds, the steric configuration of some of theatoms in the molecules of these compounds is of importance and the mostinteresting compounds have a multi-ring structure whose skeleton may berepresented by the formula (B): ##STR3## in which each of the symbols Rrepresents any of a variety of substituent groups, some of which may bequite complex, and the different groups represented by R in this formulamay be the same or different, although they are normally different fromeach other. The numbering system shown on this formula is that commonlyused in the art for the nomenclature of such compounds and is as usedherein.

In the preparation of these compounds, it is necessary to synthesise anazetidinone ring system with various substituent groups preferably inthe desired final configuration. This, in general, has proven difficult,although many attempts have been made. For example, U.S. Pat. Nos.4,895,939 and 4,772,683 describe the preparation of a compound offormula (C): ##STR4## (in which tBu represents a t-butyl group and Merepresents a methyl group) by reacting a compound of formula (D):##STR5## with t-butyldimethylsilyl trifluoroacetate, which has theformula CF₃ COOSi(CH₃)₂ tBu, in the presence of a base to give a 75:25mixture of compounds of formula (E) and (F): ##STR6## This mixture isthen reacted with a compound of formula (G): ##STR7## in the presence ofa Lewis acid, to give the desired compound of formula (C).

It has been reported that a 2R-isomer of a compound of formula (H):##STR8## which is a key intermediate in the synthesis of1β-methylcarbapenem antibiotics, can be synthesized by reacting a silylenol ether prepared from S-phenyl thiopropionate with(3R,4R)-3-[(1R)-1-t-butyldimethylsilyloxy)ethyl]-4-acetoxy-2-azetidinoneor with its 1-trimethylsilyl derivative [T. Shibata et al., TetrahedronLetters, 26, 4793 (1985); C. U. Kim et al., Tetrahedron Letters, 28, 507(1987); A. Martel et al., Can. J. Chem., 66, 1537 (1988)].

However, in the syntheses described in these reports, the 2R- and2S-isomers of the thiopropionic acid derivative of formula (H) areproduced in the ratio of 1.6:1, 1:19 and 1:9, respectively. Thus thedesired 2R-isomer is prepared in relatively minor amounts and, in mostcases, is produced in admixture with a much larger quantity of its lessuseful 2S-isomer, or, at least, with a substantial quantity of the2S-ismoer, from which its separation is difficult, expensive andinefficient.

There is, therefore, a need for a method of preparing the desiredcarbapenem antibiotic precursors which allows the required compounds tobe obtained in better yields and with the desired isomer as the majorproduct and not in admixture with substantial amounts of an unwantedisomer.

Several compounds having a thiol group attached to the 2-position of apenem or carbapenem compound are known and are thought to be of value asantibiotics. Many such compounds are prepared synthetically. Inparticular, the 1β-methylcarbapenem derivatives, which are currently ofconsiderable interest in this field, must be prepared synthetically, asno microorganism has been found which secretes them. An excellent methodof synthesizing such compounds, which overcomes many of thedisadvantages of the prior processes, is described in Japanese PatentKokai Application No. Hei 1-25780 and involves oxidizing a sulfur atomat the carbapenem 2-position to an S-oxide (i.e. a sulfinyl or sulfonylgroup) and then replacing the resulting sulfinyl or sulfonyl group by adesired mercapto group, for example as shown in the following reaction:##STR9##

However, when this reaction is carried out by conventional means inwhich an organic base is employed, in many cases the sulfenic acidformed by the substitution reaction induces the production of variouskinds of by-products, which results in a low reaction yield. Forexample, the yield of the addition-elimination reaction shown in theabove reaction scheme is said to be 22% in Japanese Patent KokaiApplication No. Hei 1-25780.

We have now surprisingly found that, if the reaction is effected in thepresence of a metal salt of a metal of Group II or III of the PeriodicTable of the Elements, in place of the organic base, yields can be muchimproved and yields of 40 to 80% or more (sometimes over 90%) can beachieved, instead of the yields of, at best, around 20% achievable inthe prior art.

BRIEF SUMMARY OF INVENTION

It is, therefore, an object of the present invention to provide a seriesof novel azetidinone derivatives which can be used as intermediates inthe preparation of a varity of carbapenem derivatives, including someuseful antibiotics.

It is accordingly another object of the present invention to provide aprocess for the preparation of 2-substituted thio derivatives.

It is a further, and more specific, object of the invention to provide aprocess for preparing such compounds which allows them to be obtained inhigh yields.

Other objects and advantages will become apparent as the descriptionproceeds.

Thus, compounds of the present invention are those compounds of formula(I): ##STR10## wherein: R¹ represents a hydrogen atom or ahydroxy-protecting group;

R² represents an alkyl group having from 1 to 6 carbon atoms, an alkoxygroup having from 1 to 6 carbon atoms, a halogen atom, an unsubstitutedphenyl group, an unsubstituted phenoxy group, or a substituted phenyl orphenoxy group having at least one substituent selected from the groupconsisting of substituents (a), defined below;

R³ represents:

a pyridyl group which is unsubstituted or is substituted by at least onesubstituent selected from the group consisting of substituents (a),defined below;

a quinolyl group which is unsubstituted or is substituted by at leastone substituent selected from the group consisting of substituents (a),defined below; or

a phenyl group which has a substituent of formula --CYNR⁵ R⁶ and nofurther substituent or has at least one substituent selected from thegroup consisting of substituents (a), defined below, where Y representsan oxygen or sulfur atom; and R⁵ and R⁶ are independently selected fromthe group consisting of alkyl groups having from 1 to 6 carbon atoms,aryl groups as defined below, and aralkyl groups in which the alkyl parthas from 1 to 6 carbon atoms and the aryl part is as defined below, or

R⁵ and R⁶ together form a group of formula --(CH₂)_(m) --(X)_(P)--(CH₂)_(n) --, wherein

m and n are independently selected from the group consisting of thecipher 0 and integers from 1 to 5, provided that (m+n) is greater than1, p is 0 or 1, and X represents an oxygen or sulfur atom or a group offormula ═R⁷, where R⁷ represents an alkyl group having from 1 to 6carbon atoms, an aliphatic carboxylic acyl group having from 1 to 6carbon atoms or an aromatic carboxylic acyl group in which the aryl partis as defined below;

R⁴ represents a hydrogen atom or an amino-protecting group; and

Z represents a sulfur atom or an oxygen atom;

said aryl groups and the aryl parts of said aralkyl groups and saidaromatic carboxylic acyl groups are carbocyclic aryl groups which havefrom 6 to 10 carbon atoms in at least one aromatic ring and which areunsubstituted or are substituted by at least one substituent selectedfrom the group consisting of substituents (a), defined below;

said substituents (a) are selected from the group consisting of alkylgroups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6carbon atoms, halogen atoms, cyano groups, nitro groups, hydroxy groups,amino groups, alkylamino groups in which the alkyl part has from 1 to 4carbon atoms, dialkylamino groups in which each alkyl part has from 1 to4 carbon atoms and alkylenedioxy groups having from 1 to 3 carbon atoms.

The invention also provides processes for preparing these compounds andfor using them to prepare carbapenem derivatives, which are described ingreater detail hereafter.

In general terms, the present invention provides a process for preparinga compound of formula (I'): ##STR11## in which: R^(1') represents ahydrogen atom or a carboxy-protecting group;

R^(2') and R^(3') are independently selected from the group consistingof hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms andgroups of formula ##STR12## where R^(5') represents a hydrogen atom or amethyl group; and R^(6') represents a hydrogen atom or ahydroxy-protecting group; or

R^(2') and R^(3') together represent a group of formula ═C(CH₃)CH₂OR^(6'), in which R^(6') is as defined above;

X' represents a sulfur atom or a group of formula >CHR^(7'), whereR^(7') represents a hydrogen atom, an alkyl group having from 1 to 6carbon atoms or an alkoxy group having from 1 to 6 carbon atoms; and

A' represents

an alkyl group which has from 1 to 6 carbon atoms and which isunsubstituted or is substituted by 1 or 2 substituents selected from thegroup consisting of substituents A', defined below,

an aryl group, as defined below,

an aralkyl group in which an alkyl group having from 1 to 6 carbon atomsis substituted by at least one aryl group as defined below,

a heterocyclic group which has from 3 to 10 ring atoms, at least one ofsaid atoms being a hetero-atom selected from the group consisting ofnitrogen, oxygen and sulfur hetero-atoms, said group being unsubstitutedor being substituted by at least one substituent selected from the groupconsisting of substituents B' on carbon atoms, substituents B^(1') onnitrogen hetero-atoms, and oxygen atoms to form a sulfinyl or sulfonylgroup on sulfur hetero-atoms, all as defined below;

a fused heterocyclic group in which a heterocyclic group as definedabove is fused to an aryl group as defined below, or

an alkyl group which has from 1 to 6 carbon atoms and which issubstituted by at least one substituent selected from the groupconsisting of the heterocyclic groups and fused heterocyclic groupsdefined above;

said aryl groups are aromatic carbocyclic groups having from 6 to 14ring carbon atoms and are unsubstituted or are substituted by at leastone substituent selected from the group consisting of substituents C',defined below;

said substituents A' are selected from the group consisting of hydroxygroups, protected hydroxy groups, amino groups, protected amino groups,groups of formula --C(═NR^(10'))NR^(11') R^(12'), where

R^(10'), R^(11') and R^(12') are independently selected from the groupconsisting of hydrogen atoms, amino-protecting groups and alkyl groupshaving from 1 to 6 carbon atoms, or R^(11') and R^(12') togetherrepresent a group of formula --(CH₂)_(n) '--, where n' is an integerfrom 2 to 6, or R^(10') and R^(11') together represent a group offormula --(CH₂)_(p) '--, where p' is 2 or 3, and

groups of formula --NR^(13') C(═NR^(14'))R^(15'), where

R^(13') and R^(14') are independently selected from the group consistingof hydrogen atoms, amino-protecting groups and alkyl groups having from1 to 6 carbon atoms, and

R^(15') represents a hydrogen atom, an alkyl group having from 1 to 6carbon atoms, an amino group or a protected amino group, or

any two of R^(13'), R^(14') and R^(15') together represent a group offormula --(CH₂)_(p) '--, where p' is 2 or 3;

said substituents B' are selected from the group consisting of

alkyl groups having from 1 to 6 carbon atoms,

alkoxy groups having from 1 to 6 carbon atoms,

hydroxy groups,

halogen atoms,

cyano groups,

nitro groups,

alkoxycarbonyl groups having from 2 to 7 carbon atoms,

carboxy groups,

oxygen atoms, to form with a ring carbon atom a carbonyl group,

cycloalkyl groups having from 3 to 7 ring carbon atoms,

alkoxyalkyl groups in which the alkoxy and alkyl parts both have from 1to 6 carbon atoms,

alkoxycarbonylalkyl groups in which the alkoxy and alkyl parts both havefrom 1 to 6 carbon atoms,

cyanoalkyl groups in which the alkyl part has from 1 to 6 carbon atoms,

haloalkyl groups having from 1 to 6 carbon atoms,

alkanoyloxy groups having from 1 to 6 carbon atoms,

azido groups,

alkylthio groups having from 1 to 6 carbon atoms,

alkylsulfinyl groups having from 1 to 6 carbon atoms,

alkylsulfonyl groups having from 1 to 6 carbon atoms,

groups of formula --NR^(8') R^(9') and groups of formula --CONR^(8')R^(9'), where R^(8') and R^(9') are independently selected from thegroup consisting of hydrogen atoms, amino-protecting groups, alkylgroups having from 1 to 6 carbon atoms and phenyl groups, or R^(8') andR^(9') together represent a group of formula --(CH₂)_(q) '--O_(r)'--(CH₂)_(s) '--, where q' and s' are independently selected from thegroup consisting of 0 and integers of from 1 to 5 and r' is 0 or 1,provided that (q'+s') is an integer of at least 2; and

groups of formulae (B-I'), (B-II'), (B-III'), (B-IV'), (B-V'), (B-VI'),(B-VII'), (B-VIII') and (B-IX'): ##STR13## in which: a' is 1, 2 or 3,

b' is 1, 1 or 2,

c' is 0 or 1,

d' is 0, 1 or 2,

e' is 0, 1 or 2,

f' is 0, 1 or 2,

g' is 0, 1 or 2,

h' is 0, 1 or 2,

R^(20') represents a hydrogen atom, an amino-protecting group, a groupof formula --COR^(26'), where

R^(26') represents an alkyl group having from 1 to 6 carbon atoms or asubstituted alkyl group which has from 1 to 6 carbon atoms and which issubstituted by at least one substituent selected from the groupconsisting of substituents A';

a group of formula --C(═NR^(16'))R^(17'), where

R^(16') and R^(17') are independently selected from the group consistingof hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, aminogroups, protected amino groups and amino-protecting groups;

an unsubstituted alkyl group having from 1 to 6 carbon atoms, or asubstituted alkyl group which has from 1 to 6 carbon atoms and which issubstituted by at least one substituent selected from the groupconsisting of substituents D', defined below.

R^(21') and R^(22') are independently selected from the group consistingof hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms, hydroxygroups and protected hydroxy groups;

R^(27') represents a hydrogen atom or an alkyl group having from 1 to 6carbon atoms;

R^(28') and R^(29') are independently selected from the group consistingof hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms,amino-protecting groups, amino groups, protected amino groups and groupsof formula --C(═NR^(16'))R^(17'), where R^(16') and R^(17') are asdefined above;

R^(30') represents a hydrogen atom, an alkyl group having from 1 to 6carbon atoms or a substituted alkyl group which has from 1 to 6 carbonatoms and which is substituted by at least one substituent selected fromthe group consisting of hydroxy groups and protected hydroxy groups;

R^(31') represents a hydrogen atom, an alkyl group having from 1 to 6carbon atoms or an amino-protecting group;

R^(32') represents a hydrogen atom, an alkyl group having from 1 to 6carbon atoms or a group of formula --NR^(28') R^(29'), in which R^(28')and R^(29') are as defined above;

E' represents an imidazolyl group or a triazolyl group;

W' represents an aromatic heterocyclic group having from 5 to 8 ringatoms, of which from 1 to 4 are nitrogen atoms, said aromaticheterocyclic group being unsubstituted or being substituted by at leastone alkyl group having from 1 to 6 carbon atoms;

Q', Q^(1'), Q^(2') and Q^(3') are independently selected from the groupconsisting of groups of formula >CH and >N;

said substituents B^(1') are selected from the group consisting of alkylgroups having from 1 to 6 carbon atoms, amino-protecting groups, groupsof formula --C(═NR^(16'))R^(17'), where R^(16') and R^(17') are asdefined above, amino-protecting groups and groups of formula--CONR^(18') R^(19'), where

R^(18') and R^(19') are independently selected from the group consistingof alkyl groups having from 1 to 6 carbon atoms and carboxylic acylgroups;

said substituents C' are selected from the group consisting of alkylgroups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6carbon atoms, halogen atoms, alkoxycarbonyl groups having from 2 to 7carbon atoms, groups of formula --CONR^(8') R^(9'), where R^(8') andR^(9') are as defined above, cyano groups, hydroxy groups and nitrogroups;

said substituents D' are selected from the group consisting of hydroxygroups, protected hydroxy groups, carboxy groups, protected carboxygroups, cyano groups, alkoxy groups having from 1 to 6 carbon atoms,alkylsulfonyl groups having from 1 to 6 carbon atoms, groups of formula--NHCOR^(23'), --NR^(24') R^(25'), --CONR^(24') R^(25') or --OCONR^(24')R^(25'), where

R^(23'), R^(24') and R^(25') are independently selected from the groupconsisting of hydrogen atoms and alkyl groups having from 1 to 6 carbonatoms,

and pharmaceutically acceptable salts and esters thereof, which processcomprises reacting a compound of formula (II): ##STR14## in whichR^(1'), R^(2'), R^(3') and X' are as defined above, k' is 1 or 2, andR^(4') represents:

an alkyl group which has from 1 to 6 carbon atoms and which isunsubstituted or is substituted by at least one substituent selectedfrom the group consisting of substituents E', defined below,

an alkenyl group which has from 2 to 6 carbon atoms and which isunsubstituted or is substituted by at least one substituent selectedfrom the group consisting of substituents E', defined below,

an aryl group, as defined above,

an aralkyl group in which an alkyl group having from 1 to 6 carbon atomsis substituted by at least one aryl group as defined above,

a cycloalkyl group which has from 3 to 7 carbon atoms and which isunsubstituted or is substituted by at least one substituent selectedfrom the group consisting of substituents C', defined above,

an aromatic heterocyclic group which has from 5 to 7 ring atoms in anaromatic ring, at least one of said atoms being a hetero-atom selectedfrom the group consisting of nitrogen, oxygen and sulfur hetero-atoms,said group being unsubstituted or being substituted by at least onesubstituent selected from the group consisting of substituents C',defined above;

a fused heterocyclic group in which an aromatic heterocyclic group asdefined above is fused to an aryl group as defined above, or

an alkyl group which has from 1 to 6 carbon atoms and which issubstituted by at least one substituent selected from the groupconsisting of the aromatic heterocyclic groups and fused heterocyclicgroups defined above; and

said substituents E' are selected from the group consisting of hydroxygroups, protected hydroxy groups, amino groups and protected aminogroups;

with a compound of formula (III'):

    A'SH                                                       (III')

in which A' is as defined above, and, if desired, removing anyprotecting groups, wherein the improvement comprises carrying out thereaction of said compound of formula (II') and said compound of formula(III') in the presence of a salt of a metal of Group II or III of thePeriodic Table of Elements.

Certain of the compounds of formula (II') used as starting materials inthe above reaction are novel compounds and also form part of the presentinvention. These novel compounds are those compounds of formula (IV'):##STR15## in which: R^(1') is as defined above;

R^(41') represents a hydrogen atom or a hydroxy-protecting group;

R^(42') represents an alkyl group having from 1 to 6 carbon atoms, analkoxy group having from 1 to 6 carbon atoms, a halogen atom, an arylgroup as defined above or an aryloxy group in which the aryl part is asdefined above;

R^(43') represents a hydrogen atom, an alkyl group having from 1 to 6carbon atoms, an alkoxy group having from 1 to 6 carbon atoms, a hydroxygroup, a halogen atom, a cyano group, a nitro group or a group offormula --NR^(8') R^(9'), where R^(8') and R^(9') are as defined above;

R^(45') and R^(46') are independently selected from the group consistingof alkyl groups having from 1 to 6 carbon atoms and aryl groups asdefined above, or R^(45') and R^(46') together represent a group offormula --(CH₂)_(q) '--O_(r) '--(CH₂)_(s) '--, where

q' and s' are independently selected from the group consisting of 0 andintegers of from 1 to 5 and r' is 0 or 1;

Y' represents an oxygen atom or a sulfur atom; and

j' is 0, 1 or 2;

and pharmaceutically acceptable salts and esters thereof.

DETAILED DESCRIPTION OF INVENTION

The steric configuration of the compounds of formula (I) important andwe therefore generally prefer those compounds of formula (I) whoseconfiguration is as shown in formula (Ia): ##STR16##

Since the compounds of formula (I) of the present invention are usefulas intermediates in the preparation of other compounds and are notthemselves used as drugs, the nature of certain groups in the compoundwhose only function is to protect a group or a part of the molecule fromattack during the preparation of those other compounds is not critical.These are the hydroxy-protecting groups which may be represented by R¹and the amino-protecting groups which may be represented by R⁴.

Where R¹ represents a hydroxy-protecting group, the nature of the groupis not critical to the invention, and it may be selected from a widerange of known groups having regard to criteria usually employed in theart and well known to those skilled in the art, without any particularrestriction. Examples of such groups include:

aliphatic acyl groups, preferably: alkanoyl groups having from 1 to 25carbon atoms, more preferably from 1 to 20 carbon atoms, still morepreferably from 1 to 6 carbon atoms, and most preferably from 1 to 4carbon atoms (such as the formyl, acetyl, propionyl, butyryl,isobutyryl, pivaloyl, valeryl, isovaleryl, hexanoyl, heptanoyl,octanoyl, lauroyl, myristoyl, tridecanoyl, palmitoyl and stearoylgroups, of which the acetyl group is most preferred); halogenatedalkanoyl groups preferably having from 2 to 6 carbon atoms, especiallyhalogenated acetyl groups (such as the chloroacetyl, dichloroacetyl,trichloroacetyl and trifluoroacetyl groups); lower alkoxyalkanoyl groupsin which the alkoxy part has from 1 to 5, preferably from 1 to 3, carbonatoms and the alkanoyl part has from 2 to 6 carbon atoms and ispreferably an acetyl group (such as the methoxyacetyl group); andunsaturated analogs of such groups, especially alkenoyl or alkynoylgroups having from 3 to 6 carbon atoms [such as the acryloyl,methacryloyl, propioloyl, crotonoyl, isocrotonoyl and(E)-2-methyl-2-butenoyl groups];

aromatic acyl groups, preferably arylcarbonyl groups, in which the arylpart has from 6 to 14, more preferably from 6 to 10, still morepreferably 6 or 10, and most preferably 6, ring carbon atoms and is acarbocyclic aromatic group, which is unsubstituted or has from 1 to 5,preferably from 1 to 3 substituents, selected from the group consistingof substituents (b), defined and exemplified below, preferably:unsubstituted groups (such as the benzoyl, α-naphthoyl and β-naphthoylgroups); halogenated arylcarbonyl groups (such as the 2-bromobenzoyl and4-chlorobenzoyl groups); lower alkyl-substituted arylcarbonyl groups, inwhich the or each alkyl substituent has from 1 to 5, preferably from 1to 4, carbon atoms (such as the 2,4,6-trimethylbenzoyl and 4-toluoylgroups); lower alkoxy-substituted arylcarbonyl groups, in which the oreach alkoxy substituent preferably has from 1 to 5, preferably from 1 to4, carbon atoms (such as the 4-anisoyl group); nitro-substitutedarylcarbonyl groups (such as the 4-nitrobenzoyl and 2-nitrobenzoylgroups); lower alkoxycarbonyl-substituted arylcarbonyl groups, in whichthe or each alkoxycarbonyl substituent preferably has from 2 to 6 carbonatoms [such as the 2-(methoxycarbonyl)benzoyl group]; andaryl-substituted arylcarbonyl groups, in which the aryl substituent isas defined above, except that, if it is substituted by a further arylgroup, that aryl group is not itself substituted by an aryl group (suchas the 4-phenylbenzoyl group);

heterocyclic groups having 5 or 6 ring atoms, of which 1 or 2 arehetero-atoms selected from the group consisting of oxygen, sulfur andnitrogen atoms, preferably oxygen or sulfur atoms, which groups may beunsubstituted or may have at least one substituent selected from thegroup consisting of substituents (b), defined and exemplified below, andoxygen atoms; examples include: the tetrahydropyranyl groups, which maybe substituted or unsubstituted, such as the tetrahydropyran-2-yl,3-bromotetrahydropyran-2-yl and 4-methoxytetrahydropyran-4-yl groups;the tetrahydrothiopyranyl groups, which may be substituted orunsubstituted, such as the tetrahydrothiopyran-2-yl and4-methoxytetrahydrothiopyran-4-yl groups; the tetrahydrofuranyl groups,which may be substituted or unsubstituted, such as thetetrahydrofuran-2-yl group; and the tetrahydrothienyl groups, which maybe substituted or unsubstituted, such as the tetrahydrothien-2-yl group;

tri-substituted silyl groups, in which all three or two or one of thesubstituents are alkyl groups having from 1 to 5, preferably from 1 to4, carbon atoms, and, correspondingly, none, one or two of thesubstituents are aryl groups, as defined above, but preferably phenyl orsubstituted phenyl groups, preferably: tri(lower alkyl)silyl groups(such as the trimethylsilyl, triethylsilyl, isopropyldimethylsilyl,t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl andtriisopropylsilyl groups); and tri(lower alkyl)silyl groups in which oneor two of the alkyl groups have been replaced by aryl groups (such asthe diphenylmethylsilyl, diphenylbutylsilyl, diphenyl-t-butylsilyl,diphenylisopropylsilyl and phenyldiisopropylsilyl groups);

alkoxylakyl groups, in which the alkoxy and alkyl parts each have from 1to 5, preferably from 1 to 4, carbon atoms, especially the alkoxymethyland alkoxyethyl groups, more especially the alkoxymethyl groups, andsuch groups which have at least one, preferably from 1 to 5, morepreferably from 1 to 3, and most preferably 1, substituents, preferably:lower alkoxymethyl groups and other alkoxyalkyl groups (such as themethoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl,propoxymethyl, isopropoxymethyl, butoxymethyl and t-butoxymethylgroups); lower alkoxy-substituted lower alkoxymethyl groups (such as the2-methoxyethoxymethyl group); halogenated lower alkoxymethyl groups[such as the 2,2,2-trichloroethoxymethyl and bis(2-chloroethoxy)methylgroups] and lower alkoxy-substituted ethyl groups (such as the1-ethoxyethyl, 1-methyl-1-methoxyethyl and 1-isopropoxyethyl groups);

other substituted ethyl groups, preferably: halogenated ethyl groups(such as the 2,2,2-trichloroethyl group); and arylselenyl-substitutedethyl groups, in which the aryl part is as defined above [such as the2-(phenylselenyl)ethyl group];

aralkyl groups, preferably alkyl groups having from 1 to 4, morepreferably from 1 to 3 and most preferably 1 or 2, carbon atoms whichare substituted with from 1 to 3 aryl groups (in which the aryl grouphas from 6 to 14 ring carbon atoms, but is otherwise as defined above),which may be unsubstituted (such as the benzyl, phenethyl,1-phenylethyl, 3-phenylpropyl, α-naphthylmethyl, β-naphthylmethyl,diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl and9-anthrylmethyl groups) or may be substituted on the aryl part with alower alkyl group ("lower" meaning "having from 1 to 6 carbon atoms"), alower alkoxy group, a nitro group, a halogen atom, a cyano group, or analkylenedioxy group having from 1 to 3 carbon atoms, preferably amethylenedioxy group [such as the 4-methylbenzyl, 2,4,6-trimethylbenzyl,3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl,2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzoyl, 4-bromobenzyl,4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, bis(2-nitrophenyl)methyl andpiperonyl groups];

alkoxycarbonyl groups, especially such groups having from 2 to 7, morepreferably 2 to 5, carbon atoms and which may be unsubstituted (such asthe methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl andisobutoxycarbonyl groups) or may be substituted with a halogen atom or atri-substituted silyl group (as defined above), e.g. a tri(loweralkylsilyl) group (such as the 2,2,2-trichloroethoxycarbonyl and2-trimethylsilylethoxycarbonyl groups);

alkenyloxycarbonyl groups in which the alkenyl part has from 2 to 6,preferably from 2 to 4, carbon atoms (such as the vinyloxycarbonyl andallyloxycarbonyl groups);

sulfo groups; and

aralkyloxycarbonyl groups, in which the aralkyl part is as defined andexemplified above, but is preferably a benzyl or phenethyl group, morepreferably a phenethyl group, and in which the aryl ring, ifsubstituted, preferably has one or two lower alkoxy or nitrosubstituents (such as the benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl and4-nitrobenzyloxycarbonyl groups).

Of the protecting groups listed above, we prefer: the tri-substitutedsilyl groups, such as the t-butyldimethylsilyl, trimethylsilyl andtriethylsilyl groups; the optionally substituted benzyloxycarbonylgroups, such as the benzyloxycarbonyl and 4-nitrobenzyloxycarbonylgroup; and the aliphatic acyl groups, such as the acetyl, chloroacetyland methoxyacetyl groups. Still more preferred are the tri-substitutedsilyl groups, especially the t-butyldimethylsilyl and trimethylsilylgroups, more especially the t-butyldimethylsilyl group.

However, the corresponding carbapenem compounds prepared from thecompounds of the present invention normally have a hydroxy group in theposition corresponding to the group of formula --OR¹, i.e. R¹ ispreferably hydrogen, and so the protecting group will be removed beforethe resulting compound is used in therapy. Its function is, therefore,simply to protect the hydroxy group during preparation of the compoundsof the present invention and during conversion of those compounds to thedesired carbapenem compounds.

Where R² represents an alkyl group having from 1 to 6 carbon atoms, thismay be a straight or branched chain group having from 1 to 6, preferablyfrom 1 to 5, carbon atoms, and examples include the methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl,isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl, 4-methylpentyl,3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl,2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, hexyl and isohexylgroups. Of these, we prefer those alkyl groups having from 1 to 4 carbonatoms, preferably the methyl, ethyl, propyl, isopropyl, butyl andisobutyl groups, more preferably a methyl or ethyl group and mostpreferably the methyl group.

Where R² represents an alkoxy group having from 1 to 6 carbon atoms,this may be a straight or branched chain group having from 1 to 6,preferably from 1 to 5, carbon atoms, and examples include the methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy,pentyloxy, isopentyloxy, neopentyloxy, 2-methylbutoxy,1-ethylpropoxy,4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy,1-methylpentyloxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy,1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy,2,3-dimethylbutoxy, 2-ethylbutoxy, hexyloxy and isohexyloxy groups. Ofthese, we prefer those alkoxy groups having from 1 to 4 carbon atoms,preferably the methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxyand t-butoxy groups, and most preferably the methoxy group.

Where R² represents a halogen atom, this may be a fluorine, chlorine,bromine or iodine atom, preferably a fluorine or chlorine atom, and mostpreferably a chlorine atom.

Where R² represents a phenyl or phenoxy group, this may be a substitutedor unsubstituted group. If substituted, the substituents are preferablyselected from the group consisting of substituents (a) defined above andexemplified below. Examples of such substituted groups include the2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-cyanophenyl,4-nitrophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl,2,4,5-trichlorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl,2,4-dichloro-3-methylphenyl, 4-aminophenyl, 4-methylaminophenyl,4-dimethylaminophenyl, 4-hydroxyphenyl, 4-methoxyphenyl,3-methoxyphenyl, 2-methoxyphenyl, 3-chloro-4-methoxyphenyl,2-chlorophenoxy, 3-chlorophenoxy, 4-chlorophenoxy, 4-cyanophenoxy,4-nitrophenoxy, 2,4-dichlorophenoxy, 2,5-dichlorophenoxy,2,4,5-trichlorophenoxy, 2-methylphenoxy, 3-methylphenoxy,4-methylphenoxy, 2,4-dichloro-3-methylphenoxy, 4-aminophenoxy,4-methylaminophenoxy, 4-dimethylaminophenoxy, 4-hydroxyphenoxy,4-methoxyphenoxy, 3-methoxyphenoxy, 2-methoxyphenoxy, and piperonyl(3,4-methylenedioxyphenyl) groups. However, the unsubstituted phenyl andphenoxy groups are preferred.

Of the groups and atoms listed above, R² preferably represents a methylgroup, an ethyl group, a methoxy group or a chlorine atom, mostpreferably a methyl group.

Where R³ represents a pyridyl group, this may be unsubstituted or it maybe substituted by at least one substituent selected from the groupconsisting of substituents (a), defined above and exemplified below. Thepyridyl group itself may be a 2-, 3- or 4-pyridyl group and, if it issubstituted, the number of substituents is limited only by the number ofsubstitutable positions (four) and possibly by steric constraints. Ingeneral the number of substituents is preferably 1 or 2, and morepreferably 1. The pyridyl group, whether unsubstituted or substituted,is preferably the 2-pyridyl group. Although the group may be substitutedby any one or more of substituents (a), exemplified below, preferredexamples of substituted groups include the 3-methyl-2-pyridyl,4-methyl-2-pyridyl, 5-methyl-2-pyridyl, 2-methyl-3-pyridyl,4-methyl-3-pyridyl, 5-methyl-3-pyridyl, 2-methyl-4-pyridyl,3-methyl-4-pyridyl, 5-methyl-4-pyridyl, 3-ethyl-2-pyridyl,4-ethyl-2-pyridyl, 5-ethyl-2-pyridyl, 2-ethyl-3-pyridyl,4-ethyl-3-pyridyl, 5-ethyl-3-pyridyl, 2-ethyl-4-pyridyl,3-ethyl-4-pyridyl, 5-ethyl-4-pyridyl, 3-chloro-2-pyridyl,4-chloro-2-pyridyl, 5-chloro-2-pyridyl, 2-chloro-3-pyridyl,4-chloro-3-pyridyl, 5-chloro-3-pyridyl, 2-chloro-4-pyridyl,3-chloro-4-pyridyl, 5-chloro-4-pyridyl, 3-methoxy-2-pyridyl,4-methoxy-2-pyridyl, 5-methoxy-2-pyridyl, 2-methoxy-3-pyridyl,4-methoxy-3-pyridyl, 5-methoxy-3-pyridyl, 2-methoxy-4-pyridyl,3-methoxy-4-pyridyl, 5-methoxy-4-pyridyl, 3-nitro-2-pyridyl,4-nitro-2-pyridyl, 5-nitro-2-pyridyl, 2-nitro-3-pyridyl,4-nitro-3-pyridyl, 5-nitro-3-pyridyl, 2-nitro-4-pyridyl,3-nitro-4-pyridyl and 5-nitro-4-pyridyl groups, of which the3-methyl-2-pyridyl, 4-methyl-2-pyridyl and 5-methyl-2-pyridyl groups aremore preferred.

Where R³ represents a quinolyl group, this may be unsubstituted or itmay be substituted by at least one substituent selected from the groupconsisting of substituents (a), defined above and exemplified below. Thequinolyl group itself may be a 2-, 3- or 4-quinolyl group and, if it issubstituted, the number of substituents is limited only by the number ofsubstitutable positions (four) and possibly by steric constraints. Ingeneral the number of substituents is preferably 1 or 2, and morepreferably 1. The quinolyl group, whether unsubstituted or substituted,is preferably the 2-quinolyl group. Although the group may besubstituted by any one or more of substituents (a), exemplified below,preferred examples of substituted groups include the3-methyl-2-quinolyl, 4-methyl-2-quinolyl, 5-methyl-2-quinolyl,2-methyl-3-quinolyl, 4-methyl-3-quinolyl, 5-methyl-3-quinolyl,2-methyl-4-quinolyl, 3-methyl-4-quinolyl, 5-methyl-4-quinolyl,3-ethyl-2-quinolyl, 4-ethyl-2-quinolyl, 5-ethyl-2-quinolyl,2-ethyl-3-quinolyl, 4-ethyl-3-quinolyl, 5-ethyl-3-quinolyl,2-ethyl-4-quinolyl, 3-ethyl-4-quinolyl, 5-ethyl-4-quinolyl,3-chloro-2-quinolyl, 4-chloro-2-quinolyl, 5-chloro-2-quinolyl,2-chloro-3-quinolyl, 4-chloro-3-quinolyl, 5-chloro-3-quinolyl,2-chloro-4-quinolyl, 3-chloro-4-quinolyl, 5-chloro-4-quinolyl,3-methoxy-2-quinolyl, 4-methoxy-2-quinolyl, 5-methoxy-2-quinolyl,2-methoxy-3-quinolyl, 4-methoxy-3-quinolyl, 5-methoxy-3-quinolyl,2-methoxy-4-quinolyl, 3-methoxy-4-quinolyl, 5-methoxy-4-quinolyl,3-nitro-2-quinolyl, 4-nitro-2-quinolyl, 5-nitro-2-quinolyl,2-nitro-3-quinolyl, 4-nitro-3-quinolyl, 5-nitro-3-quinolyl,2-nitro-4-quinolyl, 3-nitro-4-quinolyl and 5-nitro-4-quinolyl groups, ofwhich the 3-methyl-2-quinolyl, 4-methyl-2-quinolyl and5-methyl-2-quinolyl groups are more preferred.

However, the unsubstituted pyridyl and quinolyl groups are preferred,and the pyridyl group is most preferred.

Where R³ represents a phenyl group, this is substituted by a carbamoylor heterocyclic-carbonyl group of formula --CONR⁵ R⁶ or a(thiocarbamoyl) or heterocyclic-(thiocarbonyl) group of formula --CSNR⁵R⁶, in which R⁵ and R⁶ are as defined above. In addition, the phenylgroup may optionally be substituted by one or more further substitutentsselected from the group consisting of substituents (a), defined aboveand exemplified below.

Where R⁵ or R⁶ represents an alkyl group, this has from 1 to 6 carbonatoms and may be a straight or branched chain group. Examples of suchgroups are as given above in relation to the groups which may berepresented by R². Of these, the methyl, ethyl, propyl, isopropyl,butyl, isobutyl and pentyl groups are preferred, and the methyl, ethyland propyl groups are more preferred, the ethyl group being mostpreferred.

Where R⁵ or R⁶ represents an aryl group, this has from 6 to 10,preferably 6 or 10, carbon atoms, and may be, for example, a phenyl ornaphthyl (1- or 2-naphthyl) group. The group may be unsubstituted or itmay be substituted by one or more substituents selected from the groupconsisting of substituents (a), defined above and exemplified below.Examples of such substituted aryl groups include the 2-chlorophenyl,3-chlorophenyl, 4-chlorophenyl, 2-chloro-1-naphthyl,1-chloro-2-naphthyl, 1-methyl-2-naphthyl, 4-cyanophenyl, 4-nitrophenyl,2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,4,5-trichlorophenyl,2-methylphenyl, 3-methylphenyl, 4-methylphenyl,2,4-dichloro-3-methylphenyl, 4-aminophenyl, 4-methylaminophenyl,4-dimethylaminophenyl, 4-hydroxyphenyl, 4-methoxyphenyl,3-methoxyphenyl, 2-methoxyphenyl, 3-chloro-4-methoxyphenyl and piperonylgroups, of which the 2-methylphenyl, 4-methoxyphenyl, 3-chlorophenyl,4-fluorophenyl, 4-methylphenyl and 4-chlorophenyl groups are preferred.However, the unsubstituted phenyl and naphthyl groups are more preferredand the phenyl group is most preferred.

Where R⁵ or R⁶ represents an aralkyl group, the aryl group may be any ofthose exemplified above in relation to the aryl groups which may berepresented by R⁵ and R⁶, and the alkyl part may be any of those alkylgroups exemplified above in relation to the alkyl groups which may berepresented by R². Preferred examples of such groups include the benzyl,phenethyl (i.e. 2-phenylethyl), 1-phenylethyl, 3-phenylpropyl,4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 2-phenylpropyl,1-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-(2-naphthyl)ethyl,benzhydryl (i.e. diphenylmethyl) and trityl (i.e. triphenylmethyl)groups and analogs of such groups in which the phenyl and naphthylgroups are replaced by the substituted groups exemplified above inrelation to R⁵ and R⁶. Of these, the benzyl and phenethyl groups arepreferred and the benzyl group is most preferred.

Where R⁵ and R⁶ represent separate groups, these groups may be the sameor different, although it is generally most convenient if they are thesame.

Alternatively, R⁵ and R⁶ may together represent a group of formula--(CH₂)_(m) --(X)_(l) --(CH₂)_(n) --, wherein m and n are independentlyselected from the group consisting of the cipher 0 and integers from 1to 5, provided that (m+n) is greater than 1, l is 0 or 1, and Xrepresents an oxygen or sulfur atom or a group of formula ═NR⁷, where R⁷represents an alkyl group having from 1 to 6 carbon atoms, an aliphaticcarboxylic acyl group having from 1 to 6 carbon atoms or an aromaticcarboxylic acyl group in which the aryl part is as defined above. Inthis group, (m+n) must be greater than 1, and, when l is 0, preferablytotal 4, 5, 6 or 7, to form, with the nitrogen atom to which they areattached, a pyrrolidinyl, piperidyl, azepinyl or azocinyl group,respectively. When l is 1, (m+n) preferably totals 3, 4, 5 or 6, and(m-n) is preferably -1, 0 or +1; more preferably m and n are each 2.Where X represents a group of formula ═NR⁷, and R⁷ represents an alkylgroup having from 1 to 6 carbon atoms, these may be any of the alkylgroups exemplified above in relation to the alkyl groups which may berepresented by R², but the methyl and ethyl groups are preferred.Examples of aliphatic acyl groups and aromatic acyl groups which may berepresented by R⁷ include the corresponding groups exemplified above inrelation to the hydroxy-protecting groups which may be represented byR¹. Of these, the alkanoyl groups having from 1 to 4 carbon atoms(particularly the formyl, acetyl, propionyl and butyryl groups) and thebenzoyl and methyl-substituted benzoyl groups (particularly thep-toluoyl group) are preferred.

Particularly preferred groups of formula --(CH₂)_(m) --(X)_(P)--(CH₂)_(n) -- include those groups of formula:

--(CH₂)₂ --,

--(CH₂)₃ --,

--(CH₂)₄ --,

--(CH₂)₅ --,

--(CH₂)₆ --,

--(CH₂)₇ --,

--(CH₂)₈ --,

--(CH₂)₂ O(CH₂)₂ --,

--(CH₂)₂ O(CH₂)₃ --,

--(CH₂)₃ O(CH₂)₃ --,

--(CH₂)₄ O(CH₂)₄ --,

--(CH₂)₂ S(CH₂)₂ --,

--(CH₂)₃ S(CH₂)₃ --,

--(CH₂)₂ S(CH₂)₃ --,

--(CH₂)₂ NMe(CH₂)₂ --,

--(CH₂)₂ NBoz(CH₂)₂ --,

--(CH₂)₂ NAc(CH₂)₂ --,

--(CH₂)₂ NAc(CH₂)₃ --, and

--(CH₂)₂ NEt(CH₂)₃ --,

where Ac represents an acetyl group, Boz represents a benzoyl group, Etrepresents an ethyl group and Me represents a methyl group. Of these,the more preferred groups are those of formula:

--(CH₂)₄ --,

--(CH₂)₅ --,

--(CH₂)₆ --, and

--(CH₂)₂ O(CH₂)₂ --,

Where R⁴ represents a amino-protecting group, the nature of the group isnot critical to the invention, and it may be selected having regard tocriteria usually employed in the art and well known to those skilled inthe art, without any particular restriction. Examples of such groupsinclude:

tri-substituted silyl groups, in which all three or two or one of thesubstituents are alkyl groups having from 1 to 5, preferably from 1 to4, carbon atoms, and none, one or two of the substituents are arylgroups, as defined above, but preferably phenyl or substituted phenylgroups, preferably: tri(lower alkyl)silyl groups (such as thetrimethylsilyl, triethylsilyl, isopropyldimethylsilyl,t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl andtriisopropylsilyl groups); and tri(lower alkyl)silyl groups in which oneor two of the alkyl groups have been replaced by aryl groups (such asthe diphenylmethylsilyl, diphenylbutylsilyl, diphenyl-t-butylsilyl,diphenylisopropylsilyl and phenyldiisopropylsilyl groups);

aliphatic acyl groups, preferably: alkanoyl groups having from 1 to 25carbon atoms, more preferably from 1 to 20 carbon atoms, still morepreferably from 1 to 6 carbon atoms, and most preferably from 1 to 4carbon atoms (such as the formyl, acetyl, propionyl, butyryl,isobutyryl, pivaloyl, valeryl, isovaleryl, hexanoyl, heptanoyl,octanoyl, lauroyl, myristoyl, tridecanoyl, palmitoyl and stearoylgroups, of which the acetyl group is most preferred); halogenatedalkanoyl groups having from 2 to 6 carbon atoms, especially halogenatedacetyl groups (such as the chloroacetyl, dichloroacetyl, trichloroacetyland trifluoroacetyl groups); lower alkoxyalkanoyl groups in which thealkoxy part has from 1 to 5, preferably from 1 to 3, carbon atoms andthe alkanoyl part has from 2 to 6 carbon atoms and is preferably anacetyl group (such as the methoxyacetyl group); and unsaturated analogsof such groups, especially alkenoyl or alkynoyl groups having from 3 to6 carbon atoms [such as the acryloyl, methacryloyl, propioloyl,crotonoyl, isocrotonoyl and (E)-2-methyl-2-butanoyl groups]; and

aromatic acyl groups, preferably arylcarbonyl groups, in which the arylpart has from 6 to 14, more preferably from 6 to 10, still morepreferably 6 or 10, and most preferably 6, ring carbon atoms and is acarbocyclic group, which is unsubstituted or has from 1 to 5, preferablyfrom 1 to 3 substituents, selected from the group consisting ofsubstituents (b), defined and exemplified below, preferably:unsubstituted groups (such as the benzoyl, α-naphthoyl and β-naphthoylgroups); halogenated arylcarbonyl groups (such as the 2-bromobenzoyl and4-chlorobenzoyl groups); lower alkyl-substituted arylcarbonyl groups, inwhich the or each alkyl substituent has from 1 to 5, preferably from 1to 4, carbon atoms (such as the 2,4,6-trimethylbenzoyl and 4-toluoylgroups); lower alkoxy-substituted arylcarbonyl groups, in which the oreach alkoxy substituent preferably has from 1 to 5, preferably from 1 to4, carbon atoms (such as the 4-anisoyl group); nitro-substitutedarylcarbonyl groups (such as the 4-nitrobenzoyl and 2-nitrobenzoylgroups); lower alkoxycarbonyl-substituted arylcarbonyl groups, in whichthe or each alkoxycarbonyl substituent preferably has from 2 to 6 carbonatoms [such as the 2-(methoxycarbonyl)benzoyl group]; andaryl-substituted arylcarbonyl groups, in which the aryl substituent isas defined above, except that, if it is substituted by a further arylgroup, that aryl group is not itself substituted by an aryl group (suchas the 4-phenylbenzoyl group).

Of these, the tri-substituted silyl groups are preferred and thetrimethylsilyl and t-butyldimethylsilyl groups are most preferred.

Examples of the groups and atoms which may be included in substituents(a) are:

alkyl groups having from 1 to 6 carbon atoms, such as those exemplifiedabove in relation to R² ;

alkoxy groups having from 1 to 6 carbon atoms, such as those exemplifiedabove in relation to R² ;

halogen atoms, such as those exemplified above in relation to R² ;

cyano groups, nitro groups, hydroxy groups and amino groups;

alkylamino groups in which the alkyl part has from 1 to 4 carbon atoms,such as the methylamino, ethylamino, propylamino, isopropylamino,butylamino, isobutylamino, sec-butylamino and t-butylamino groups;

dialkylamino groups in which each alkyl part has from 1 to 4 carbonatoms, such as the dimethylamino, diethylamino, dipropylamino,diisopropylamino, dibutylamino, diisobutylamino, methylethylamino andmethylbutylamino groups; and

alkylenedioxy groups having from 1 to 3 carbon atoms, such as themethylenedioxy, ethylenedioxy, trimethylenedioxy and propylenedioxygroups, of which the methylenedioxy group is most preferred.

Examples of the groups and atoms which may be included in substituents(b) are those groups and atoms exemplified above in relation tosubstituents (a), and:

alkoxycarbonyl groups, especially such groups having from 2 to 7, morepreferably 2 to 5, carbon atoms and which may be unsubstituted (such asthe methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl andisobutoxycarbonyl groups) or substituted with a halogen atom or atri-substituted silyl group, e.g. a tri(lower alkylsilyl) group (such asthe 2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonylgroups); and

aryl groups, such as those exemplified above in relation to R⁵ and R⁶.

Of the compounds of the present invention, one class of preferredcompounds are those compounds of formulae (I) and (Ia), in which:

R¹ represents a hydrogen atom or a hydroxy-protecting group;

R² represents an alkyl group having from 1 to 6 carbon atoms, an alkoxygroup having from 1 to 6 carbon atoms, a halogen atom, an unsubstitutedphenyl group or an unsubstituted phenoxy group;

R³ represents:

a pyridyl group which is unsubstituted or is substituted by at least onesubstituent selected from the group consisting of substituents (a₁),defined below; or

a quinolyl group which is unsubstituted or is substituted by at leastone substituent selected from the group consisting of substituents (a₁),defined below;

R⁴ represents a hydrogen atom or an amino-protecting group; and

Z represents a sulfur atom;

said substituents (a₁) are selected from the group consisting of alkylgroups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6carbon atoms and halogen atoms.

Of these, a more preferred class of compounds of the present inventionare those compounds of formulae (I) and (Ia), in which:

R¹ represents:

a hydrogen atom;

a tri-substituted silyl group, in which all three or two or one of thesubstituents are alkyl groups having from 1 to 5 carbon atoms, and none,one or two of the substituents are aryl groups, as defined above;

an aliphatic acyl group having from 1 to 6 carbon atoms;

a halogenated alkanoyl group having from 2 to 6 carbon atoms;

an alkoxyalkanoyl group in which the alkoxy part has from 1 to 5 carbonatoms and the alkanoyl part has from 2 to 6 carbon atoms; or

an aralkyloxycarbonyl group, in which the aryl part is as defined above,and the alkyl part has from 1 to 4 carbon atoms;

R² represents a methyl, ethyl, methoxy or ethoxy group;

R³ represents:

a pyridyl group which is unsubstituted or is substituted by at least onesubstituent selected from the group consisting of substituents (a₂),defined below; or

a quinolyl group which is unsubstituted or is substituted by at leastone substituent selected from the group consisting of substituents (a₂),defined below;

R⁴ represents a hydrogen atom or a tri-substituted silyl group, in whichall three or two or one of the substituents are alkyl groups having from1 to 5 carbon atoms, and none, one or two of the substituents are arylgroups, as defined above; and

Z represents a sulfur atom;

said substituents (a₂) are selected from the group consisting of methyl,ethyl, methoxy and ethoxy groups.

Of these, the most preferred class of compounds of the present inventionare those compounds of formulae (I) and (Ia), in which:

R¹ represents:

a hydrogen atom;

a tri-substituted silyl group, in which all three or two or one of thesubstituents are alkyl groups having from 1 to 5 carbon atoms, and none,one or two of the substituents are aryl groups, as defined above;

an aliphatic acyl group having from 1 to 6 carbon atoms;

a halogenated alkanoyl group having from 2 to 6 carbon atoms;

an alkoxyalkanoyl group in which the alkoxy part has from 1 to 5 carbonatoms and the alkanoyl part has from 2 to 6 carbon atoms; or

an aralkyloxycarbonyl group, in which the aryl part is as defined above,and the alkyl part has from 1 to 4 carbon atoms;

R² represents a methyl or ethyl group;

R³ represents:

a pyridyl group which is unsubstituted or is substituted by at least onemethyl group; or

a quinolyl group which is unsubstituted or is substituted by at leastone methyl group;

R⁴ represents a hydrogen atom or a tri-substituted silyl group, in whichall three or two or one of the substituents are alkyl groups having from1 to 5 carbon atoms, and none, one or two of the substituents are arylgroups, as defined above; and

Z represents a sulfur atom.

An alternative preferred class of compounds of the present invention arethose compounds of formulae (I) and (Ia), in which:

R¹ represents a hydrogen atom or a hydroxy-protecting group;

R² represents a methyl group;

R³ represents a phenyl group which has a substituent of formula --CYNR⁵R⁶ and no further substituent or has at least one substituent selectedfrom the group consisting of substituents (a₁), defined below, where

Y represents an oxygen or sulfur atom; and

R⁵ and R⁶ are independently selected from the group consisting of alkylgroups having from 1 to 6 carbon atoms, aryl groups as defined above,and aralkyl groups in which the alkyl part has from 1 to 6 carbon atomsand the aryl part is as defined above, or

R⁵ and R⁶ together form a group of formula --(CH₂)_(m) --(X)_(P)--(CH₂)_(n) --, wherein

m and n are independently selected from the group consisting of thecipher 0 and integers from 1 to 5, provided that (m+n) is greaterthan 1. l is 0 or 1, and X represents an oxygen or sulfur atom or agroup of formula ═NR⁷, where R⁷ represents an alkyl group having from 1to 6 carbon atoms, an aliphatic carboxylic acyl group having from 1 to 6carbon atoms or an aromatic carboxylic acyl group in which the aryl partis as defined above;

R⁴ represents a hydrogen atom or an amino-protecting group; and

Z represents a sulfur atom;

said substituents (a₁) are selected from the group consisting of alkylgroups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6carbon atoms and halogen atoms.

An alternative more preferred class of compounds of the presentinvention are those compounds of formulae (I) and (Ia), in which:

R¹ represents:

a hydrogen atom;

a tri-substituted silyl group, in which all three or two or one of thesubstituents are alkyl groups having from 1 to 5 carbon atoms, and none,one or two of the substituents are aryl groups, as defined above;

an aliphatic acyl group having from 1 to 6 carbon atoms;

a halogenated alkanoyl group having from 2 to 6 carbon atoms;

an alkoxyalkanoyl group in which the alkoxy part has from 1 to 5 carbonatoms and the alkanoyl part has from 2 to 6 carbon atoms; or

an aralkyloxycarbonyl group, in which the aryl part is as defined above,and the alkyl part has from 1 to 4 carbon atoms;

R² represents a methyl group;

R³ represents a phenyl group which has a substituent of formula --CONR⁵R⁶ and no further substituent or has at least one substituent selectedfrom the group consisting of substituents (a₂), defined below, where

R⁵ and R⁶ are independently selected from the group consisting of alkylgroups having from 1 to 3 carbon atoms, phenyl groups which areunsubstituted or are substituted by at least one substituent selectedfrom the group consisting of substituents (a₂), defined below, andaralkyl groups in which the alkyl part has 1 or 2 carbon atoms and thearyl part is a phenyl group which is unsubstituted or is substituted byat least one substituent selected from the group consisting ofsubstituents (a₂), defined below, or

R⁵ and R⁶ together form a group of formula --(CH₂)_(m) --(X)_(P)--(CH₂)_(n) --, wherein

m and n are independently selected from the group consisting of thecipher 0 and integers from 1 to 5, provided that (m+n) is greater than1, l is 0 or 1, and X represents an oxygen or sulfur atom or a group offormula ═NR⁷, where R⁷ represents a methyl group, an ethyl group, analiphatic carboxylic acyl group having from 2 to 4 carbon atoms or abenzoyl group which is unsubstituted or is substituted by at least onesubstituent selected from the group consisting of substituents (a₂),defined below;

R⁴ represents a hydrogen atom or a tri-substituted silyl group, in whichall three or two or one of the substituents are alkyl groups having from1 to 5 carbon atoms, and none, one or two of the substituents are arylgroups, as defined above; and

Z represents a sulfur atom;

said substituents (a₂) are selected from the group consisting of methyl,ethyl, methoxy and ethoxy groups.

An alternative most preferred class of compounds of the presentinvention are those compounds of formulae (I) and (Ia), in which:

R¹ represents:

a hydrogen atom;

a tri-substituted silyl group, in which all three or two or one of thesubstituents are alkyl groups having from 1 to 5 carbon atoms, and none,one or two of the substituents are aryl groups, as defined above;

an aliphatic acyl group having from 1 to 6 carbon atoms;

a halogenated alkanoyl group having from 2 to 6 carbon atoms;

an alkoxyalkanoyl group in which the alkoxy part has from 1 to 5 carbonatoms and the alkanoyl part has from 2 to 6 carbon atoms; or

an aralkyloxycarbonyl group, in which the aryl part is as defined above,and the alkyl part has from 1 to 4 carbon atoms;

R² represents a methyl group;

R³ represents a phenyl group which has a substituent of formula --CONR⁵R⁶ and no further substituent or has at least one substituent selectedfrom the group consisting of methyl and methoxy groups, where

R⁵ and R⁶ are independently selected from the group consisting of alkylgroups having from 1 to 3 carbon atoms, or

R⁵ and R⁶ together form a group of formula

--(CH₂)₄ --

--(CH₂)₅ --

--(CH₂)₆ -- or

--(CH₂)₂ --O--(CH₂)₂ --;

R⁴ represents a hydrogen atom; and

Z represents a sulfur atom.

The compounds of the present invention necessarily contain severalassymetric carbon atoms and can, therefore, form optical isomers,including, for example, that shown above as formula (Ia). In addition,depending upon the nature of the various substituent groups, otheroptical and geometric isomers may be possible. Although all such isomersare shown herein by a single formula, the present invention embraces theuse of all such isomers as well as mixtures thereof. Where a mixture ofthe compounds of the present invention is obtained, these may beseparated by conventional resolution techniques. Alternatively, inappropriate cases, a mixture of isomers may be used. However, it shouldbe remembered that it is an advantage of the present invention that thedesired 1β-isomer can be obtained readily and in a good yield.

Specific examples of compounds of the present invention are shown in thefollowing formulae (I-1) to (I-3), in which the various substituentgroups are as defined in the corresponding one of Tables 1 to 3, i.eTable 1 relates to formula (I-1), Table 2 relates to formula (I-2) andTable 3 relates to formula (I-3). In the Tables 1 to 3, the followingabbreviations are used:

    ______________________________________                                                Ac          acetyl                                                            Boz         benzoyl                                                           Bu          buty                                                              iBu         isobutyl                                                          tBu         t-butyl                                                           Bz          benzyl                                                            Et          ethyl                                                             Me          methyl                                                            Ph          phenyl                                                            Pn          pentyl                                                            Pr          propyl                                                            iPr         isopropyl                                                         Prn         propionyl                                                         Pyr         pyridyl                                                           Quin        quinolyl                                                  ______________________________________                                         ##STR17##

                  TABLE 1                                                         ______________________________________                                        Cpd.                                                                          No.  R.sup.1      R.sup.2                                                                              R.sup.3  R.sup.4                                     ______________________________________                                        1-1  tBuMe.sub.2 Si--                                                                           Me     2-Pyr    H                                           1-2  tBuMe.sub.2 Si--                                                                           Me     3-Me-2-Pyr                                                                             H                                           1-3  tBuMe.sub.2 Si--                                                                           Me     4-Me-2-Pyr                                                                             H                                           1-4  tBuMe.sub.2 Si--                                                                           Me     5-Me-2-Pyr                                                                             H                                           1-5  tBuMe.sub.2 Si--                                                                           Me     2-Quin   H                                           1-6  tBuMe.sub.2 Si--                                                                           Et     2-Pyr    H                                           1-7  tBuMe.sub.2 Si--                                                                           Me     3-MeO-2-Pyr                                                                            H                                           1-8  tBuMe.sub.2 Si--                                                                           Cl     2-Pyr    H                                           1-9  tBuMe.sub.2 Si--                                                                           OMe    2-Pyr    H                                           1-10 Me.sub.3 Si--                                                                              Me     2-Pyr    H                                           1-11 Me.sub.3 Si--                                                                              Me     3-Me-2-Pyr                                                                             H                                           1-12 BzO.CO--     Me     2-Pyr    H                                           1-13 p-NO.sub.2 BzO.CO--                                                                        Me     2-Pyr    H                                           1-14 Ac           Me     2-Pyr    H                                           1-15 ClCH.sub.2 CO--                                                                            Me     2-Pyr    H                                           1-16 BzO.CO--     Me     3-Me-2-Pyr                                                                             H                                           1-17 p-NO.sub.2 BzO.CO--                                                                        Me     3-Me-2-Pyr                                                                             H                                           1-18 BzO.CO--     Me     2-Quin   H                                           1-19 Me.sub.3 Si--                                                                              Et     2-Pyr    H                                           1-20 tBuMe.sub.2 Si--                                                                           Me     2-Pyr    tBuMe.sub.2 Me.sub.2 Si--                   1-21 tBuMe.sub.2 Si--                                                                           Me     2-Pyr    Ac                                          1-22 tBuMe.sub.2 Si--                                                                           Me     2-Pyr    Boz                                         1-23 tBuMe.sub.2 Si--                                                                           Me     2-Pyr    Prn                                         1-24 tBuMe.sub.2 Si--                                                                           Me     3-Me-2-Pyr                                                                             tBuMe.sub.2 Si--                            1-25 tBuMe.sub.2 Si--                                                                           Me     3-Me-2-Pyr                                                                             Ac                                          1-26 tBuMe.sub.2 Si--                                                                           Me     3-Me-2-Pyr                                                                             Boz                                         1-27 tBuMe.sub.2 Si--                                                                           Me     3-Me-2-Pyr                                                                             Prn                                         1-28 H            Me     2-Pyr    H                                           1-29 H            Me     3-Me-2-Pyr                                                                             H                                           1-30 H            Me     4-Me-2-Pyr                                                                             H                                           1-31 H            Me     5-Me-2-Pyr                                                                             H                                           1-32 H            Me     2-Quin   H                                           1-33 H            Et     2-Pyr    H                                           1-34 H            Me     3-MeO-2-Pyr                                                                            H                                           1-35 H            Cl     2-Pyr    H                                           1-36 H            OMe    2-Pyr    H                                           1-37 H            Me     2-Pyr    tBuMe.sub.2 Si--                            1-38 H            Me     2-Pyr    Ac                                          1-39 H            Me     2-Pyr    Boz                                         1-40 H            Me     2-Pyr    Prn                                         1-41 H            Me     3-Me-2-Pyr                                                                             tBuMe.sub.2 Si--                            1-42 H            Me     3-Me-2-Pyr                                                                             Ac                                          1-43 H            Me     3-Me-2-Pyr                                                                             Boz                                         1-44 H            Me     3-Me-2-Pyr                                                                             Prn                                         ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        Cpd.                                                                          No.  R.sup.1       R.sup.3a                                                                              R.sup.5                                                                             R.sup.6                                                                              Y    Z                                ______________________________________                                        2-1  tBuMe.sub.2 Si--                                                                            H       Me    Me     O    S                                2-2  tBuMe.sub.2 Si--                                                                            H       Et    Et     O    S                                2-3  tBuMe.sub.2 Si--                                                                            H       Pr    Pr     O    S                                2-4  tBuMe.sub.2 Si--                                                                            H       iPr   iPr    O    S                                2-5  tBuMe.sub.2 Si--                                                                            H       Me    Et     O    S                                2-6  tBuMe.sub.2 Si--                                                                            H       iBu   iBu    O    S                                2-7  tBuMe.sub.2 Si--                                                                            H       Bu    Bu     O    S                                2-8  tBuMe.sub.2 Si--                                                                            H       Et    Pr     O    S                                2-9  tBuMe.sub.2 Si--                                                                            H       Pn    Pn     O    S                                2-10 Me.sub.3 Si-- H       Et    Et     O    S                                2-11 Me.sub.3 Si-- H       Me    Me     O    S                                2-12 Me.sub.3 Si-- H       Pr    Pr     O    S                                2-13 Me.sub.3 Si-- H       Me    Et     O    S                                2-14 Me.sub.3 Si-- H       Et    Pr     O    S                                2-15 Me.sub.3 Si-- H       iBu   iBu    O    S                                2-16 tBuMe.sub.2 Si--                                                                            H       Me    Ph     O    S                                2-17 tBuMe.sub.2 Si--                                                                            H       Et    Ph     O    S                                2-18 tBuMe.sub.2 Si--                                                                            H       Pr    Ph     O    S                                2-19 tBuMe.sub.2 Si--                                                                            H       Bu    Ph     O    S                                2-20 tBuMe.sub.2 Si--                                                                            H       Et    2-MePh O    S                                2-21 tBuMe.sub.2 Si--                                                                            H       Et    4-MeOPh                                                                              O    S                                2-22 tBuMe.sub.2 Si--                                                                            H       Et    3-ClPh O    S                                2-23 tBuMe.sub.2 Si--                                                                            H       Bu    4-FPh  O    S                                2-24 tBuMe.sub.2 Si--                                                                            H       Me    4-MePh O    S                                2-25 tBuMe.sub.2 Si--                                                                            H       Me    4-ClPh O    S                                2-26 p-NO.sub.2 BzO.CO--                                                                         H       Me    Et     O    S                                2-27 p-NO.sub.2 BzO.CO--                                                                         H       Et    Et     O    S                                2-28 p-NO.sub.2 BzO.CO--                                                                         H       Et    Pr     O    S                                2-29 p-NO.sub.2 BzO.CO--                                                                         H       Me    Me     O    S                                2-30 p-NO.sub.2 BzO.CO--                                                                         H       Pr    Pr     O    S                                2-31 p-NO.sub.2 BzO.CO--                                                                         H       Et    Bu     O    S                                2-32 tBuMe.sub.2 Si--                                                                            H       Et    Bz     O    S                                2-33 tBuMe.sub.2 Si--                                                                            H       Et    2-PhEt O    S                                2-34 tBuMe.sub.2 Si--                                                                            H       Me    Bz     O    S                                2-35 tBuMe.sub.2 Si--                                                                            H       Me    2-PhEt O    S                                2-36 tBuMe.sub.2 Si--                                                                            H       Et    Bz     O    S                                2-37 tBuMe.sub.2 Si--                                                                            3-Cl    Et    Et     O    S                                2-38 tBuMe.sub.2 Si--                                                                            3-Me    Et    Et     O    S                                2-39 tBuMe.sub.2 Si--                                                                            3-OMe   Et    Et     O    S                                2-40 tBuMe.sub.2 Si--                                                                            6-Me    Et    Et     O    S                                2-41 tBuMe.sub.2 Si--                                                                            6-Cl    Et    Et     O    S                                2-42 tBuMe.sub.2 Si--                                                                            6-OMe   Et    Et     O    S                                2-43 tBuMe.sub.2 Si--                                                                            3-Cl    Me    Me     O    S                                2-44 tBuMe.sub.2 Si--                                                                            3-Me    Me    Me     O    S                                2-45 tBuMe.sub.2 Si--                                                                            3-OMe   Me    Me     O    S                                2-46 tBuMe.sub.2 Si--                                                                            6-Cl    Me    Me     O    S                                2-47 tBuMe.sub.2 Si--                                                                            6-OMe   Me    Me     O    S                                2-48 tBuMe.sub.2 Si--                                                                            6-Me    Me    Me     O    S                                2-49 tBuMe.sub.2 Si--                                                                            3-Cl    Me    Et     O    S                                2-50 tBuMe.sub.2 Si--                                                                            3-Me    Me    Et     O    S                                2-51 tBuMe.sub.2 Si--                                                                            3-OMe   Me    Et     O    S                                2-52 tBuMe.sub.2 Si--                                                                            3-Cl    Et    Pr     O    S                                2-53 tBuMe.sub.2 Si--                                                                            3-Me    Et    Pr     O    S                                2-54 tBuMe.sub.2 Si--                                                                            3-OMe   Et    Pr     O    S                                2-55 tBuMe.sub.2 Si--                                                                            6-Me    Et    Et     O    O                                2-56 tBuMe.sub.2 Si--                                                                            H       Et    Et     O    O                                2-57 tBuMe.sub.2 Si--                                                                            H       Me    Me     O    O                                2-58 tBuMe.sub.2 Si--                                                                            H       Pr    Pr     O    O                                2-59 tBuMe.sub.2 Si--                                                                            3-Me    Et    Et     O    O                                2-60 tBuMe.sub.2 Si--                                                                            H       Et    Et     S    S                                2-61 tBuMe.sub.2 Si--                                                                            H       Me    Me     S    S                                2-62 tBuMe.sub.2 Si--                                                                            H       Pr    Pr     S    S                                2-63 tBuMe.sub.2 Si--                                                                            6-Me    Et    Et     S    S                                2-64 tBuMe.sub.2 Si--                                                                            6-Me    Pr    Pr     S    S                                2-65 tBuMe.sub.2 Si--                                                                            6-Me    Me    Me     S    S                                2-66 H             H       Me    Me     O    S                                2-67 H             H       Et    Et     O    S                                2-68 H             H       Pr    Pr     O    S                                2-69 H             H       iPr   iPr    O    S                                2-70 H             H       Me    Et     O    S                                2-71 H             H       iBu   iBu    O    S                                2-72 H             H       Bu    Bu     O    S                                2-73 H             H       Et    Pr     O    S                                2-74 H             H       Pn    Pn     O    S                                2-75 H             3-Me    Et    Et     O    S                                2-76 H             6-Me    Et    Et     O    S                                2-77 H             3-OMe   Me    Me     O    S                                2-78 H             6-OMe   Me    Me     O    S                                2-79 H             3-Cl    Et    Pr     O    S                                2-80 H             H       Et    Et     O    O                                2-81 H             H       Me    Me     O    O                                2-82 H             H       Pr    Pr     O    O                                2-83 H             3-Me    Et    Et     O    O                                2-84 H             H       Et    Et     S    S                                2-85 H             H       Me    Me     S    S                                2-86 H             H       Pr    Pr     S    S                                2-87 H             6-Me    Et    Et     S    S                                2-88 H             6-Me    Pr    Pr     S    S                                2-89 H             6-Me    Me    Me     S    S                                ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                        Cpd.                                                                          No.  R.sup.1    R.sup.3a                                                                              A             Y   Z                                   ______________________________________                                        3-1  tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.2 --                                                                       O   S                                   3-2  tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.3 --                                                                       O   S                                   3-3  tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.4 --                                                                       O   S                                   3-4  tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.5 --                                                                       O   S                                   3-5  tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.6 --                                                                       O   S                                   3-6  tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.7 --                                                                       O   S                                   3-7  tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.8 --                                                                       O   S                                   3-8  tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.2 O(CH.sub.2).sub.2 --                                                     O   S                                   3-9  tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.2 O(CH.sub.2).sub.3 --                                                     O   S                                   3-10 tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.3 O(CH.sub.2).sub.3 --                                                     O   S                                   3-11 tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.4 O(CH.sub.2).sub.4 --                                                     O   S                                   3-12 tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.2 S(CH.sub.2).sub.2 --                                                     O   S                                   3-13 tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.3 S(CH.sub.2).sub.3 --                                                     O   S                                   3-14 tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.2 S(CH.sub.2).sub.3 --                                                     O   S                                   3-15 tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.3 S(CH.sub.2).sub.3 --                                                     O   S                                   3-16 tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.2 NMe(CH.sub.2).sub.2 --                                                   O   S                                   3-17 tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.2 NBoz(CH.sub.2).sub.2 --                                                  O   S                                   3-18 tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.2 NAc(CH.sub.2).sub.2 --                                                   O   S                                   3-19 tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.2 NAc(CH.sub.2).sub.3 --                                                   O   S                                   3-20 tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.2 NEt(CH.sub.2).sub.3 --                                                   O   S                                   3-21 tBuMe.sub.2 Si--                                                                         3-Me    --(CH.sub.2).sub.2 O(CH.sub.2).sub.2 --                                                     O   S                                   3-22 tBuMe.sub.2 Si--                                                                         3-OMe   --(CH.sub.2).sub.2 O(CH.sub.2).sub.2 --                                                     O   S                                   3-23 tBuMe.sub.2 Si--                                                                         3-Cl    --(CH.sub.2).sub.2 O(CH.sub.2).sub.2 --                                                     O   S                                   3-24 tBuMe.sub.2 Si--                                                                         3-OEt   --(CH.sub.2).sub.2 O(CH.sub.2).sub.2 --                                                     O   S                                   3-25 tBuMe.sub.2 Si--                                                                         6-Me    --(CH.sub.2).sub.2 O(CH.sub.2).sub.2 --                                                     O   S                                   3-26 tBuMe.sub.2 Si--                                                                         6-OMe   --(CH.sub.2).sub.2 O(CH.sub.2).sub.2 --                                                     O   S                                   3-27 tBuMe.sub.2 Si--                                                                         6-Cl    --(CH.sub.2).sub.2 O(CH.sub.2).sub.2 --                                                     O   S                                   3-28 tBuMe.sub.2 Si--                                                                         3-Me    --(CH.sub.2).sub.2 --                                                                       O   S                                   3-29 tBuMe.sub.2 Si--                                                                         3-OMe   --(CH.sub.2).sub.2 --                                                                       O   S                                   3-30 tBuMe.sub.2 Si--                                                                         3-Cl    --(CH.sub.2).sub.2 --                                                                       O   S                                   3-31 tBuMe.sub.2 Si--                                                                         6-OMe   --(CH.sub.2).sub.6 --                                                                       O   S                                   3-32 tBuMe.sub.2 Si--                                                                         6-Me    --(CH.sub.2).sub.6 --                                                                       O   S                                   3-33 tBuMe.sub.2 Si--                                                                         6-Cl    --(CH.sub.2).sub.6 --                                                                       O   S                                   3-34 tBuMe.sub.2 Si--                                                                         3-Me    --(CH.sub.2).sub.3 --                                                                       O   S                                   3-35 tBuMe.sub.2 Si--                                                                         3-OMe   --(CH.sub.2).sub.3 --                                                                       O   S                                   3-36 tBuMe.sub.2 Si--                                                                         3-Cl    --(CH.sub.2).sub.3 --                                                                       O   S                                   3-37 tBuMe.sub.2 Si--                                                                         3-Me    --(CH.sub.2).sub.3 --                                                                       O   S                                   3-38 tBuMe.sub.2 Si--                                                                         6-OMe   --(CH.sub.2).sub.3 --                                                                       O   S                                   3-39 tBuMe.sub.2 Si--                                                                         6-Cl    --(CH.sub.2).sub.3 --                                                                       O   S                                   3-40 tBuMe.sub.2 Si--                                                                         3-Me    --(CH.sub.2).sub.4 --                                                                       O   S                                   3-41 tBuMe.sub.2 Si--                                                                         3-OMe   --(CH.sub.2).sub.4 --                                                                       O   S                                   3-42 tBuMe.sub.2 Si--                                                                         3-Cl    --(CH.sub.2).sub.4 --                                                                       O   S                                   3-43 tBuMe.sub.2 Si--                                                                         6-Me    --(CH.sub.2).sub.4 --                                                                       O   S                                   3-44 tBuMe.sub.2 Si--                                                                         6-OMe   --(CH.sub.2).sub.4 --                                                                       O   S                                   3-45 tBuMe.sub.2 Si--                                                                         6-Cl    --(CH.sub.2).sub.4 --                                                                       O   S                                   3-46 tBuMe.sub.2 Si--                                                                         3-Me    --(CH.sub.2).sub.5 --                                                                       O   S                                   3-47 tBuMe.sub.2 Si--                                                                         3-OMe   --(CH.sub.2).sub.5 --                                                                       O   S                                   3-48 tBuMe.sub.2 Si--                                                                         3-Cl    --(CH.sub.2).sub.5 --                                                                       O   S                                   3-49 tBuMe.sub.2 Si--                                                                         6-Me    --(CH.sub.2).sub.5 --                                                                       O   S                                   3-50 tBuMe.sub.2 Si--                                                                         6-OMe   --(CH.sub.2).sub.5 --                                                                       O   S                                   3-51 tBuMe.sub.2 Si--                                                                         6-Cl    --(CH.sub.2).sub.5 --                                                                       O   S                                   3-52 tBuMe.sub.2 Si--                                                                         3-Me    --(CH.sub.2).sub.6 --                                                                       O   S                                   3-53 tBuMe.sub.2 Si--                                                                         3-OMe   --(CH.sub.2).sub.6 --                                                                       O   S                                   3-54 tBuMe.sub.2 Si--                                                                         3-Cl    --(CH.sub.2).sub.6 --                                                                       O   S                                   3-55 tBuMe.sub.2 Si--                                                                         3-Me    --(CH.sub.2).sub.2 S(CH.sub.2).sub.2 --                                                     O   S                                   3-56 tBuMe.sub.2 Si--                                                                         3-OMe   --(CH.sub.2).sub.2 S(CH.sub.2).sub.2 --                                                     O   S                                   3-57 tBuMe.sub.2 Si--                                                                         3-Cl    --(CH.sub.2).sub.2 S(CH.sub.2).sub.2 --                                                     O   S                                   3-58 tBuMe.sub.2 Si--                                                                         3-Cl    --(CH.sub.2).sub.2 NAc(CH.sub.2).sub.2 --                                                   O   S                                   3-59 tBuMe.sub.2 Si--                                                                         3-OMe   --(CH.sub.2).sub.2 NAc(CH.sub.2).sub.2 --                                                   O   S                                   3-60 tBuMe.sub.2 Si--                                                                         3-Me    --(CH.sub.2).sub.2 NAc(CH.sub.2).sub.2 --                                                   O   S                                   3-61 tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.5 --                                                                       O   O                                   3-62 tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.4 --                                                                       O   O                                   3-63 tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.5 --                                                                       S   S                                   3-64 tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.4 --                                                                       S   S                                   3-65 tBuMe.sub.2 Si--                                                                         3-Me    --(CH.sub.2).sub.5 --                                                                       S   S                                   3-66 tBuMe.sub.2 Si--                                                                         6-Me    --(CH.sub.2).sub.6 --                                                                       S   S                                   3-67 tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.6 --                                                                       O   O                                   3-68 tBuMe.sub.2 Si--                                                                         6-Me    --(CH.sub.2).sub.6 --                                                                       O   O                                   3-69 tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.4 --                                                                       O   S                                   3-70 tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.5 --                                                                       O   S                                   3-71 tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.6 --                                                                       O   S                                   3-72 tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.2 O(CH.sub.2).sub.2 --                                                     O   S                                   3-73 tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.2 S(CH.sub.2).sub.2 --                                                     O   S                                   3-74 tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.2 NBoz(CH.sub.2).sub.2 --                                                  O   S                                   3-75 tBuMe.sub.2 Si--                                                                         H       --(CH.sub.2).sub.2 NAc(CH.sub.2).sub.2 --                                                   O   S                                   3-76 tBuMe.sub.2 Si--                                                                         3-Me    --(CH.sub.2).sub.2 O(CH.sub.2).sub.2 --                                                     O   S                                   3-77 tBuMe.sub.2 Si--                                                                         3-OMe   --(CH.sub.2).sub.2 O(CH.sub.2).sub.2 --                                                     O   S                                   3-78 H          3-Me    --(CH.sub.2).sub.4 --                                                                       O   S                                   3-79 H          3-OMe   --(CH.sub.2).sub.4 --                                                                       O   S                                   3-80 H          3-Cl    --(CH.sub.2).sub.4 --                                                                       O   S                                   3-81 H          6-Me    --(CH.sub.2).sub.4 --                                                                       O   S                                   3-82 H          6-OMe   --(CH.sub.2).sub.4 --                                                                       O   S                                   3-83 H          6-Cl    --(CH.sub.2).sub.4 --                                                                       O   S                                   3-84 H          3-Me    --(CH.sub.2).sub.5 --                                                                       O   S                                   3-85 H          3-OMe   --(CH.sub.2).sub.5 --                                                                       O   S                                   3-86 H          3-Cl    --(CH.sub.2).sub.5 --                                                                       O   S                                   3-87 H          6-Me    --(CH.sub.2).sub.5 --                                                                       O   S                                   3-88 H          6-OMe   --(CH.sub.2).sub.5 --                                                                       O   S                                   3-89 H          6-Cl    --(CH.sub.2).sub.5 --                                                                       O   S                                   3-90 H          3-Me    --(CH.sub.2).sub.2 S(CH.sub.2).sub.2 --                                                     O   S                                   3-91 H          3-Me    --(CH.sub.2).sub.2 NAc(CH.sub.2).sub.2 --                                                   O   S                                   3-92 H          H       --(CH.sub.2).sub.5 --                                                                       O   O                                   3-93 H          H       --(CH.sub.2).sub.4 --                                                                       O   O                                   3-94 H          H       --(CH.sub.2).sub.5 --                                                                       S   S                                   3-95 H          H       --(CH.sub.2).sub.4 --                                                                       S   S                                   3-96 H          3-Me    --(CH.sub.2).sub.5 --                                                                       S   S                                   3-97 H          6-Me    --(CH.sub.2).sub.6 --                                                                       S   S                                   3-98 H          H       --(CH.sub.2).sub.6 --                                                                       O   O                                   3-99 H          6-Me    --(CH.sub.2).sub.6 --                                                                       O   O                                   ______________________________________                                    

Of the compounds listed above, the following are preferred, that is tosay Compounds No. 1-1, 1-5, 1-10, 1-13, 1-14, 1-16, 1-20, 1-22, 1-24,1-26, 1-28, 1-32, 1-37, 1-39, 1-41, 1-43, 2-1, 2-2, 2-3, 2-6, 2-16,2-26, 2-27, 2-28, 2-29, 2-30, 2-31, 2-37, 2-38, 2-39, 2-40, 2-41, 2-42,2-55, 2-56, 2-59, 2-60, 2-63, 2-66, 2-68, 2-69, 2-70, 2-71, 2-75, 3-3,3-4, 3-5, 3-8, 3-21, 3-25, 3-46, 3-47, 3-48, 3-49, 3-50, 3-51, 3-61,3-63, 3-65, 3-69, 3-70, 3-71, 3-72, 3-76, 3-84, 3-85, 3-86, 3-87, 3-88,3-89, 3-92, 3-94 and 3-96, and the following are more preferred, that isto say Compounds No. 1-1, 1-5, 1-10, 1-13, 1-20, 1-22, 1-24, 1-26, 1-28,1-32, 1-37, 1-39, 1-41, 1-43, 2-1, 2-2, 2-3, 2-6, 2-16, 2-26, 2-27,2-28, 2-29, 2-30, 2-31, 2-40, 2-56, 2-60, 2-63, 2-66, 2-68, 2-69, 2-70,2-71, 3-3, 3-4, 3-5, 3-8, 3-21, 3-25, 3-61, 3-63, 3-65, 3-69, 3-70, 3-71and 3-72. The most preferred specific compounds of the present inventionare Compounds No.:

1-1.(3S,4S)-3[(1R)-1-t-Butyldimethylsilyloxyethyl]-4-[(1R)-(2-pyridylthiocarbonyl)ethyl]azetidin-2-one;

1-5.(3S,4S)-3-[(1R)-1-t-Butyldimethylsilyloxyethyl]-4-[(1R)-2-quinolinethiocarbonyl)ethyl]azetidin-2-one;

1-10.(3S,4S)-3[(1R)-1-Trimethylsilyloxyethyl]-4-[(1R)-(2-pyridylthiocarbonyl)ethyl]azetidin-2-one;

1-13.(3S,4S)-3[(1R)-1-p-Nitrobenzyloxycarbonyloxyethyl]-4-[(1R)-(2-pyridylthiocarbonyl)ethyl]azetidin-2-one;

1-28.(3S,4S)-3[(1R)-1-Hydroxyethyl]-4-[(1R)-(2-pyridylthiocarbonyl)ethyl]azetidin-2-one;

1-32.(3S,4S)-3-[(1R)-1-Hydroxyethyl]-4-[(1R)-(2-quinolinethiocarbonyl)ethyl]azetidin-2-one;

2-2. S-2-Diethylcarbamoylphenyl2(R)-{(3S,4S)-3-[1(R)-(t-butyldimethylsilyloxy)ethyl]-2-oxo-4-azetidinyl}thiopropionate;

2-3. S-2-Dipropylcarbamoylphenyl2(R)-{(3S,4S)-3-[1(R)-(t-butyldimethylsilyloxy)ethyl]-2-oxo-4-azetidinyl}thiopropionate;

2-56. 2-Diethylcarbamoylphenyl2(R)-{(3S,4S)-3-[1(R)-(t-butyldimethylsilyloxy)ethyl]-2-oxo-4-azetidinyl}propionate;

2-60. S-2-[Diethyl(thiocarbamoyl)]phenyl2(R)-{(3S,4S)-3-[1(R)-(t-butyldimethylsilyloxy)ethyl]-2-oxo-4-azetidinyl}thiopropionate;

2-67. S-2-Diethylcarbamoylphenyl2(R)-{(3S,4S)-3-[1(R)-hydroxyethyl]-2-oxo-4-azetidinyl}thiopropionate;

3-3. S-2-(1-Pyrrolidinylcarbonyl)phenyl2(R)-{(3S,4S)-3-[1(R)-(t-butyldimethylsilyloxy)ethyl]-2-oxo-4-azetidinyl}thiopropionate;

3-4. S-2-(1-Piperidylcarbonyl)phenyl2(R)-{(3S,4S)-3-[1(R)-(t-butyldimethylsilyloxy)ethyl]-2-oxo-4-azetidinyl}thiopropionate;

3-5. S-2-(1-Azepinylcarbonyl)phenyl2(R)-{(3S,4S)-3-[1(R)-(t-butyldimethylsilyloxy)ethyl]-2-oxo-4-azetidinyl}thiopropionate;

3-8. S-2-Morpholinocarbonylphenyl2(R)-{(3S,4S)-3-[1(R)-(t-butyldimethylsilyloxy)ethyl]-2-oxo-4-azetidinyl}thiopropionate.

The compounds of the present invention can be prepared by a variety ofmethods, whose general techniques are known in the art for thepreparation of compounds of this type. For example, they may be preparedby reacting a compound of formula (II): ##STR18## in which R², R³ and Zare as defined above, and R⁸, R⁹ and R¹⁰ are the same or different andeach represents an alkyl group having from 1 to 4 carbon atoms or aphenyl group, with a compound of formula (III): ##STR19## in which R¹and R⁴ are as defined above, and R¹¹ represents an acyloxy,alkylsulfonyl, arylsulfonyl, alkylsufinyl or arylsulfinyl group, all ofwhich are as more precisely defined and exemplified below.

More preferably, the compound of formula (III) has the configurationshown in formula (IIIa): ##STR20## to produce a compound of formula(Ia): ##STR21##

Examples of the alkyl groups which may be represented by R⁸, R⁹ and R¹⁰include the methyl, ethyl, propyl, isopropyl, butyl, sec-butyl andt-butyl groups. Examples of preferred groups of formula SiR⁸ R⁹ R¹⁰include the t-butyldimethylsilyl, trimethylsilyl, triethylsilyl,triisopropylsilyl and t-butyldiphenylsilyl groups.

The acyloxy groups which may be represented by R¹¹ are carboxylicacyloxy groups which may be aliphatic or aromatic. In the case of thealiphatic acyloxy groups, these preferably have from 1 to 6, morepreferably from 2 to 4, carbon atoms and may be alkanoyloxy,haloalkanoyloxy or alkenoyloxy groups, the alkanoyloxy groups beingpreferred. Examples of such groups include the acetoxy, propionyloxy andbutyryloxy groups. In the case of the aromatic acyloxy groups, these arearylcarbonyloxy groups and the aryl part may be as defined andexemplified above. A preferred such group is the benzoyloxy group. Inthe case of the alkylsulfonyl and alkylsulfinyl groups, the alkyl partshave from 1 to 6, preferably from 1 to 4, carbon atoms and examples ofthe alkyl moieties of such groups include the methyl, ethyl, propyl andisopropyl groups. In the case of the arylsulfonyl and arylsulfinylgroups, the aryl part may be as defined and exemplified above, andexamples of the aryl moieties of such groups include the phenyl andp-tolyl groups. Preferably R¹¹ represents an acetoxy, benzoyloxy,phenylsulfonyl, phenylsulfinyl, tolylsulfinyl or methylsulfinyl group.

In this reaction, a silyl enol ether of formula (II) is reacted with anazetidinone derivative of formula (III). This reaction normally andpreferably takes place in the presence of a solvent and in the presenceof a Lewis acid.

Examples of Lewis acids which may be used in the reaction include: zincchloride, zinc bromide, zinc iodide and boron trifluoride etherate. Ofthese, we prefer to use zinc chloride or zinc iodide.

The reaction is normally and preferably effected in the presence of asolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor on the reagents involved and that it can dissolve the reagents, atleast to some extent. Examples of suitable solvents include: halogenatedhydrocarbons, especially halogenated aliphatic hydrocarbons, such asmethylene chloride, chloroform and 1,2-dichloroethane; ethers such astetrahydrofuran and 1,2-dimethoxyethane; and nitriles, such asacetonitrile. Of these, we prefer to use methylene chloride, chloroformor 1,2-dichloroethane.

The reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature of from -10° C. to 70° C. and more preferably from 10° C. to50° C. The time required for the reaction may also vary widely,depending on many factors, notably the reaction temperature and thenature of the reagents and solvent employed. However, provided that thereaction is effected under the preferred conditions outlined above, aperiod of from 10 minutes to 24 hours will usually suffice.

The compound of formula (I) thus obtained can be recovered from thereaction mixture by any conventional method. For example, one suitablerecovery procedure comprises adding a solvent, such as methylenechloride or ethyl acetate, to the reaction mixture, separating andwashing the organic layer with water and finally separating the desiredcompound by suitable means, such as thin layer chromatography or flashchromatography through silica gel, or purifying it by means ofcrystallization or recrystallization.

The silyl enol ether of formula (II), used as a starting material inthis reaction, can be prepared by reacting a compound of formula (IV):

    R.sup.2 CH.sub.2.CO.ZR.sup.3                               (IV)

in which R², R³ and Z are as defined above, with an active silylcompound of formula (V):

    R.sup.8 R.sup.9 R.sup.10 SiW                               (V)

in which R⁸, R⁹ and R¹⁰ are as defined above, and W represents a leavinggroup, for example a halogen atom, such as a chlorine atom, or asulfonyloxy group, such as a trifluoromethanesulfonyloxy group, in thepresence of a base.

The reaction is normally and preferably effected in the presence of asolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor on the reagents involved and that it can dissolve the reagents, atleast to some extent. Examples of suitable solvents include: ethers suchas diethyl ether, 1,2-dimethoxyethane and tetrahydrofuran; andhydrocarbons, especially aliphatic hydrocarbons, such as hexane orcyclohexane; mixtures of of any two or more of these solvents may alsobe employed.

The yield of the reaction can be improved by adding one or more of thefollowing solvents to one or more of the solvents listed above. Examplesof such additional solvents include: hexamethylphosphoric triamide(HMPA), N,N-dimethylformamide, N,N-dimethylacetamide,N,N'-dimethylpropyleneurea, N-methylpyrrolidone and N-methylpiperidone.

Examples of bases which may be used in the reaction include lithium,sodium or potassium salts of diisopropylamine, hexamethyldisilazane,dicyclohexylamine or 2,2,6,6-tetramethylpiperidine.

In some cases, the addition of one or more additional bases as well asthe bases listed above will improve the yield of the compound of formula(II). Examples of such bases include tertiary amines, such astriethylamine.

The reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature of from -90° C. to 20° C. and more preferably from -78° C.to -20° C. The time required for the reaction may also vary widely,depending on many factors, notably the reaction temperature and thenature of the reagents and solvent employed. However, provided that thereaction is effected under the preferred conditions outlined above, aperiod of from 5 minutes to 4 hours and more preferably from 10 minutesto 30 minutes will usually suffice.

The resulting compound of formula (II) can then be recovered from thereaction mixture by conventional means. For example, it can be recoveredin a good yield by adding water, a saturated aqueous solution of sodiumhydrogencarbonate or triethylamine to the reaction mixture, extractingthe mixture with an organic solvent and then purifying it by means ofcolumn chromatography or distillation.

Where R³ represents a phenyl group R² represents a methyl group and Zrepresents a sulfur atom, the resulting compound of formula (IV) is asubstituted S-phenyl thiopropionate, which can be used as a startingcompound in the above reaction. This may be prepared as shown in thefollowing Reaction Schemes A and B: ##STR22##

In the above formulae, R^(3a), R⁵ and R⁶ are as defined above. R¹²represents an aryl group (as defined above), such as a phenyl or tolylgroup, and R¹³ represents a lower alkyl group having from 1 to 6 carbonatoms, preferably from 1 to 4 carbon atoms, such as a methyl or ethylgroup.

In Reaction Scheme A, a substituted S-phenyl thiopropionate, that is tosay a compound of formula (IVa), can be prepared from a compound offormula (VI), which, in turn, can readily be obtained by reacting a2,2'-dithiobenzoic acid derivative with a halogenating agent, such asthionyl chloride.

In Step A1, a secondary amine, R⁵ R⁶ NH, is reacted with the compound offormula (VI) in the presence of an organic amine, such as triethylamine,or an inorganic base such, as sodium carbonate, to give the compound offormula (VII). In Step A2, this compound of formula (VII) is reactedwith propionic anhydride in the presence of a metal having reducingactivity, such as zinc.

Alternatively, in Reaction Scheme B, a compound of formula (IVa) isprepared using a thiosalicylic acid derivative of formula (VIII) as thestarting material.

In Step B1 of this reaction scheme, the thiol group of a compound offormula (VIII) is protected by reacting the compound of formula (VIII)with an aromatic acyl halide, such as benzoyl chloride, to give theprotected compound of formula (IX).

In Step B2, the compound of formula (IX) is reacted with a secondaryamine, R⁵ R⁶ NH, in the presence of a dehydrating condensing agent, suchas 2-chloro-1-methylpyridinium iodide, to produce an amide compound offormula (X).

In Step B3, the aromatic acyl protecting group, R¹² CO, is removed bytreating the compound of formula (X) with a base, such as sodiummethoxide, to give a compound of formula (XI).

In Step B4, the thiol group of the compound of formula (XI) ispropionylated by reacting it with an active derivative of propionicacid, such as propionyl chloride or propionic anhydride, in the presenceof a base, to give the desired substituted S-phenyl thiopropionate offormula (IVa).

Alternatively, the compound of formula (XI) can also be prepared from ananthranilic acid derivative of formula (XII) by conventional means (e.g.as disclosed in Organic Syntheses Coll. Vol. III, page 809, thedisclosure of which is incorporated herein by reference) via Steps B5and B6. In Step B5, a compound of formula (XII) is diazotized and thenreacted with potassium S-ethyl dithiocarbonate, to give a compound offormula (XIII). In Step B6, this compound of formula (XIII) ishydrolysed with a base, such as potassium hydroxide, to give thecompound of formula (XI).

Reaction Scheme B illustrates the preparation of compounds of formula(IV) in which R³ represents a substituted phenyl group, Y represents anoxygen atom and Z represents a sulfur atom, that is a compound offormula (IVa). Corresponding compounds in which Y represents a sulfuratom or Z represents an oxygen atom can be prepared as illustrated inthe following Reaction Schemes C and D: ##STR23##

In the above formulae, R^(3a), R⁵ and R⁶ are as defined above and Halrepresents a halogen atom.

In Reaction Scheme C, the carbonyl group forming part of the amido groupat the 2-position of the compound of formula (IVa) is converted to athiocarbonyl group by reaction with a thiolating agent, such asLawesson's reagent or phosphorus pentasulfide. This reaction is wellknown in the art and may be carried out using solvents, reactiontemperatures and reaction times as are conventional and well known.

In Step D1 of Reaction Scheme D, the carboxy group at the 2-position ofthe compound of formula (IVa) is halogenated, preferably chlorinated,using a conventional halogenating agent, such as oxalyl chloride, oxalylbromide, thionyl chloride or thionyl bromide, and using conventionalhalogenating conditions, to give the compound of formula (XVI). Thiscompound of formula (XVI) is then reacted with a secondary amine offormula R⁵ R⁶ NH in the presence of an organic tertiary amine, such astriethylamine, or of an inorganic base, such as sodium carbonate, togive the desired compound of formula (XVII).

The azetidinone derivatives of formula (I) in accordance with thepresent invention can readily be converted to the correspondingcarbapenem compounds by reaction with an appropriate mercaptanderivative of formula R¹⁴ SH, which may be effected by conventionalmeans (e.g. as described in Japanese Patent Application Kokai No. Sho60-19764) to produce a compound of formula (XVIII), which can then becyclised by conventional means (e.g. as described in Japanese PatentPublication No. Sho 62-54427), to give a carbapenem derivative offormula (XIX), as shown in the following Reaction Schemes E and Ea:##STR24##

In these formulae, Z, R¹, R², R³ and R⁴ are as defined above and R¹⁴represents a variety of organic groups of a type commonly employed, atthe indicated position, in carbapenem derivatives. As can be seen fromReaction Scheme E', the configuration at the azetidine 3-position and atthe carbon atom to which the group represented by R² is attached areconserved, and so this provides a convenient and efficient way ofproducing these valuable compounds.

In contrast, the compound of formula (C), described in U.S. Pat. Nos.4,895,939 and 4,772,683, referred to above, does not appear suitable forthis reaction because it does not easily react with a mercaptan offormula R¹⁴ SH in the first step of Reaction Scheme E, and cannot,therefore, readily form the compound of formula (XVII). On the otherhand, in the reactions described by T. Shibata et al. [TetrahedronLetters, 26, 4793 (1985)], C. U. Kim et al. [Tetrahedron Letters, 28,507 (1987)] and A. Martel et al. [Can. J. Chem., 66, 1537 (1988)] thedesired 2R-isomer is produced in a relatively low yield in admixturewith a large quantity of the unwanted 2S-isomer, and so is difficult andexpensive to isolate.

In the compounds of formula (I'), (II') and (IV'), where R^(1')represents a carboxy-protecting group, this may be any group commonlyemployed in the synthesis of β-lactam antibiotics, and, in the case ofthe compounds of formulae (II') and (IV'), which are simplyintermediates, there is no particular restriction; in the case of thedesired compounds of formula (I'), which may be used in therapy, caremay need to be taken in selecting the protecting group, if a protectinggroup is present. More preferably, in the case of the compounds offormula (I'), R^(1') represents a hydrogen atom or is an ester group, asdescribed in greater detail hereafter. Examples of such protectinggroups include:

lower alkyl groups having from 1 to 6, preferably from 1 to 4, carbonatoms, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl,1-ethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methyl-pentyl,1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethyl-butyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,3-dimethylbutyl, 2-ethylbutyl, hexyl and isohexyl groups; of these, weprefer those alkyl groups having from 1 to 4 carbon atoms, preferablythe methyl, ethyl and t-butyl groups;

aralkyl groups, which are preferably alkyl groups which have from 1 to4, preferably from 1 to 3, more preferably 1 or 2, and most preferably1, carbon atoms and which are substituted by at least one (morepreferably 1, 2 or 3) aryl groups, as defined above, such as the benzyl,diphenylmethyl, triphenylmethyl, 4-nitrobenzyl, 2-nitrobenzyl,1-naphthylmethyl, α-methylbenzyl, α,α-dimethylbenzyl, 1-phenylethyl,phenethyl (i.e. 2-phenylethyl), 3-phenylpropyl and 4-phenylbutyl groups,of which the benzyl, diphenylmethyl, 4-nitrobenzyl and 2-nitrobenzylgroups are preferred;

alkenyl groups having from 2 to 6, preferably 3 or 4, carbon atoms, andwhich are optionally substituted by one or more halogen atoms, such asthe vinyl, allyl, 2-chloroallyl or 2-methylallyl groups;

haloalkyl groups having from 1 to 6, preferably from 1 to 4, carbonatoms, such as the trifluoromethyl, trichloromethyl, difluoromethyl,dichloromethyl, dibromomethyl, fluoromethyl, chloromethyl, bromomethyl,iodomethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, 2-bromoethyl,2-chloroethyl, 2-fluoroethyl, 2,2-dibromoethyl, 3-chloropropyl,3,3,3-trichloropropyl, perfluoroethyl, 4-fluorobutyl, 5-bromopentyl,6-chlorohexyl and 6,6,6-trifluorohexyl groups, preferably the2,2,2-trichloroethyl or 2,2,2-tribromoethyl group; and

tri-substituted silylethyl groups, in which all three or two or one ofthe substituents are alkyl groups having from 1 to 5, preferably from 1to 4, carbon atoms, and none, one or two of the substituents are arylgroups, as defined above, but preferably phenyl or substituted phenylgroups, preferably: 1- or 2-[tri(lower alkyl)silyl]ethyl groups, such asthe 2-(trimethylsilyl)ethyl, 2-(triethylsilyl)ethyl,2-(isopropyldimethylsilyl)ethyl, 2-(t-butyldimethylsilyl)ethyl,2-(methyldiisopropylsilyl)ethyl, 2-(methyldi-t-butylsilyl)ethyl and2-(triisopropylsilyl)ethyl groups; and 1- or 2-[tri(loweralkyl)silyl]ethyl groups in which one or two of the alkyl groups havebeen replaced by aryl groups, such as the 2-(diphenylmethylsilyl)ethyl,2-(diphenylbutylsilyl)ethyl, 2-(diphenyl-t-butylsilyl)ethyl,2-(diphenylisopropylsilyl)ethyl and 2-(phenyldiisopropylsilyl)ethylgroups, especially the 2-(trimethylsilyl)ethyl group;

acyloxyalkyl groups, in which the acyl part is an alkanoyl group havingfrom 1 to 6, preferably from 1 to 5, carbon atoms and the alkyl part hasfrom 1 to 6, preferably 1 or 2, carbon atoms, such as theformyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl,valeryloxymethyl, isovaleryloxymethyl, pivaloyloxymethyl,hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl,1-propionyloxyethyl, 1-butyryloxyethyl, 1-valeryloxyethyl,1-isovaleryloxyethyl, 1-pivaloyloxyethyl, 1-hexanoyloxyethyl,1-formyloxypropyl, 1-acetoxypropyl, 1-pivaloyloxypropyl, 1-acetoxybutyl,1-acetoxypentyl and 1-acetoxyhexyl groups, preferably the acetoxymethyl,pivaloyloxymethyl and 1-acetoxyethyl groups;

alkoxycarbonyloxyalkyl groups in which the alkoxy and alkyl parts eachhave from 1 to 6, preferably from 1 to 4, carbon atoms, such as theethoxycarbonyloxymethyl, 1-(ethoxycarbonyloxy)ethyl,1-(isopropoxycarbonyloxy)ethyl and t-butoxycarbonyloxymethyl groups;cycloalkoxycarbonyloxyalkyl groups in which the cycloalkyl part has from3 to 7, preferably 5 or 6, ring carbon atoms and may be unsubstituted orsubstituted by at least one substituent selected from the groupconsisting of substituents C', defined above and exemplified below, butparticularly an alkyl group having from 1 to 6, preferably from 1 to 4and more preferably 1 or 2, carbon atoms, and the alkyl part has from 1to 6, preferably from 1 to 4 and more preferably 1 or 2, carbon atoms,such the 1-(cyclohexyloxycarbonyloxy)ethyl and(1-methylcyclohexyl)oxycarbonyloxymethyl groups;

(5-alkyl or 5-aryl-2-oxo-1,3-dioxolen-4-yl)methyl groups in which thealkyl part has from 1 to 4, preferably 1 or 2, carbon atoms and the arylpart is as defined above, but is preferably a phenyl group, such as the(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl and(5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl groups; and

the 3-phthalidyl group.

The above acyloxyalkyl groups, alkoxycarbonyloxyalkyl groups,cycloalkoxycarbonyloxyalkyl groups, (5-alkyl or5-aryl-2-oxo-1,3-dioxolen-4-yl)methyl groups and 3-phthalidyl group arecapable of hydrolysis in vivo and are therefore particularly preferred,especially for those cases where they are to be retained in the finalproduct for therapeutic use.

Where R^(2'), R^(3') or R^(4') represents an alkyl group, this may be astraight or branched chain group having from 1 to 6, preferably from 1to 4, carbon atoms, and examples include the methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl,neopentyl, 2-methylbutyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl,2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,3-dimethylbutyl, 2-ethylbutyl, hexyl and isohexyl groups. Of these, weprefer those alkyl groups having from 1 to 4 carbon atoms, preferablythe methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl andt-butyl groups, and most preferably the methyl and ethyl groups.

Where R^(2') or R^(3') represents a group of formula ##STR25## andR^(6') represents a hydroxy-protecting group, the hydroxy-protectinggroup may be selected from any protecting groups known in the art foruse in β-lactam antibiotics. Examples of such groups are given by T. W.Green in "Protective Groups in Organic Synthesis", John Wiley & Sons;and by J. F. W. McOmie in "Protective Groups in Organic Chemistry",Plenum Press, the disclosures of which are incorporated herein byreference. More specifically, preferred such protecting groups includethe:

substituted silyl groups, in which the silyl group has up to 3, andpreferably 3, substituents selected from alkyl groups having from 1 to 6carbon atoms and phenyl groups which are unsubstituted or have at leastone substituent selected from substituents C' defined above andexemplified below, for example a trimethylsilyl, triethylsilyl,t-butyldimethylsilyl or t-butyldiphenylsilyl group;

aralkyl groups, which are preferably alkyl groups which have from 1 to4, preferably from 1 to 3, more preferably 1 or 2, and most preferably1, carbon atoms and which are substituted by at least one (morepreferably 1, 2 or 3) aryl groups, as defined above, such as the benzyl,diphenylmethyl, triphenylmethyl, 4-methoxybenzyl, 4-nitrobenzyl,2-nitrobenzyl, 1-naphthylmethyl, α-methylbenzyl, α,α-dimethylbenzyl,1-phenylethyl, phenethyl, 3-phenylpropyl and 4-phenylbutyl groups, ofwhich the benzyl, 4-methoxybenzyl, 4-nitrobenzyl and 2-nitrobenzylgroups are preferred;

oxycarbonyl groups, including:

aralkyloxycarbonyl groups, in which the aralkyl part may be as definedand exemplified above, preferably the benzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl andbenzhydryloxycarbonyl groups;

alkenyloxycarbonyl groups in which the alkenyl part has from 2 to 6,preferably 2 or 3, carbon atoms and may be unsubstituted or may besubstituted by at least one (preferably from 1 to 3, more preferably 1)halogen atom, such as the allyloxycarbonyl, 2-chloroallyloxycarbonyl and2-methylallyloxycarbonyl groups;

alkoxycarbonyl groups which have in total from 2 to 7 carbon atoms, thatis in which the alkyl part has from 1 to 6 carbon atoms and may be anyof the alkyl groups exemplified above, and which may be unsubstituted ormay be substituted by at least one (preferably from 1 to 3, morepreferably 1 or 3) halogen atom, such as the2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl andt-butoxycarbonyl groups; and

substituted silylalkoxycarbonyl groups, in which the alkoxycarbonyl partis as defined and exemplified above and the substituted silyl part isalso as defined and exemplified above, such as the2-(trimethylsilyl)ethoxycarbonyl group;

ether groups, including:

oxygen-containing heterocyclic groups, for example the substituted andunsubstituted tetrahydropyranyl and tetrahydrofuranyl groups, such asthe tetrahydropyranyl group;

alkoxyalkyl groups in which the alkoxy and alkyl parts each have from 1to 6, preferably from 1 to 4 and more preferably 1 or 2, carbon atoms,such as the methoxymethyl and 1-ethoxyethyl groups;

substituted silylalkoxyalkyl groups, in which the alkoxyalkyl part is asdefined and exemplified above and the substituted silyl part is also asdefined and exemplified above, such as the2-(trimethylsilyl)ethoxymethyl group; and

and alkanoyl and haloalkanoyl groups which have from 1 to 6 carbon atoms(2 to 6, in the case of the haloalkanoyl groups), such as the acetyl,propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl andchloroacetyl groups.

Where R^(7') represents an alkyl group having from 1 to 6 carbon atoms,this may be a straight or branched chain group, and examples include themethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl,pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl,4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl,3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl,1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl,hexyl and isohexyl groups. Of these, we prefer those alkyl groups havingfrom 1 to 4 carbon atoms, preferably the methyl, ethyl, propyl,isopropyl, butyl and sec-butyl groups, and most preferably the methylgroup.

Where R^(7') represents an alkoxy group having from 1 to 6 carbon atoms,this may be a straight or branched chain group, and examples include themethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,t-butoxy, pentyloxy, isopentyloxy, neopentyloxy, 2-methylbutoxy,1-ethylpropoxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy,1-methylpentyloxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy,1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy,2,3-dimethylbutoxy, 2-ethylbutoxy, hexyloxy and isohexyloxy groups. Ofthese, we prefer those alkoxy groups having from 1 to 4 carbon atoms,preferably the methoxy, ethoxy, propoxy, isopropoxy, butoxy andsec-butoxy groups, and most preferably the methoxy group.

Where A' represents an alkyl group, this may be a straight or branchedchain group having from 1 to 6, preferably from 1 to 4, carbon atoms,and examples include the methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl,2-methylbutyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl,2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,3-dimethylbutyl, 2-ethylbutyl, hexyl and isohexyl groups. Of these, weprefer those alkyl groups having from 1 to 4 carbon atoms, preferablythe methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl andt-butyl groups, and most preferably the methyl and ethyl groups.

Where A' represents a substituted alkyl group, the alkyl part may be anyof the unsubstituted groups defined and exemplified above, and thesubstituents are selected from substituents A', which include:

hydroxy groups,

protected hydroxy groups, such as those defined and exemplified above inrelation to R^(6'),

amino groups,

protected amino groups, in which the protecting group may be chosen fromany amino-protecting group well known in the field of β-lactamchemistry, and there may be one or two such groups, preferably one suchgroup, for example

acyl groups, including alkanoyl and haloalkanoyl groups as defined abovein relation to the hydroxy-protecting groups which may be represented byR^(6'), preferably the formyl, acetyl, chloroacetyl and propionylgroups, and arylcarbonyl groups (in which the aryl part may be asdefined above and exemplified below), preferably the benzoyl group, and

oxycarbonyl groups, which may be as defined above in relation to thehydroxy-protecting groups which may be represented by R^(6'), preferablythe benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, allyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl,t-butoxycarbonyl and 2-(trimethylsilyl)ethoxycarbonyl groups;

groups of formula --C(═NR^(10'))NR^(11') R^(12') and --NR^(13')C(═NR^(14'))R^(15'), where R^(10'), R^(11'), R^(12'), R^(13') andR^(14') are independently selected from the group consisting of hydrogenatoms, amino-protecting groups (for example as defined and exemplifiedabove) and alkyl groups having from 1 to 6 carbon atoms (for example asdefined and exemplified in relation to the alkyl groups which may berepresented by A', preferably a methyl or ethyl group), or R^(11') andR^(12') together represent a group of formula --(CH₂)_(n) '--, where n'is an integer from 2 to 6, or R^(10') and R^(11') together represent agroup of formula --(CH₂)_(p) '--, where p' is 2 or 3, and R^(15')represents a hydrogen atom, an alkyl group having from 1 to 6 carbonatoms (for example as defined and exemplified in relation to the alkylgroups which may be represented by A, preferably a methyl, ethyl orpropyl group), an amino group or a protected amino group (for example asdefined and exemplified above), or any two of R^(13'), R^(14') andR^(15') together represent a group of formula --(CH₂)_(p) '--, where p'is 2 or 3.

Where A' represents an aryl group, this is a carbocyclic aromatic grouphaving from 6 to 14, preferably from 6 to 10, more preferably 6 or 10,and most preferably 6, ring carbon atoms in one or more aromatic rings.The group may also be unsubstituted or substituted, and, if substituted,the substituents are selected from the group consisting of substituentsC', defined above and exemplified below. In the case of the substitutedgroups, there is no particular limitation on the number of substituentson the aryl group, except such as may be imposed by the number ofsubstitutable positions or possibly by steric constraints, but, ingeneral, from 1 to 5 substituents are preferred, from 1 to 4 being morepreferred and 1, 2 or 3 being most preferred. Also, where the group issubstituted, it is preferred that it should not be further substitutedby a group which is also substituted by another aryl group. Specificexamples of the aromatic groups include the phenyl, α- or β-naphthyl,indenyl, phenanthrenyl and anthracenyl groups, of which we prefer thosearomatic hydrocarbon groups having from 6 to 10 ring carbon atoms,particularly the phenyl, α-naphthyl and β-naphthyl groups, the phenylgroup being most preferred.

Where the aryl group is substituted, the substituents are selected fromthe group consisting of substituents C', which include:

alkyl groups having from 1 to 6 carbon atoms, which may be a straight orbranched chain group, and examples include the methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl,neopentyl, 2-methylbutyl, 1-ethylpropyl, 4-methylpentyl, 3-methylpentyl,2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,3-dimethylbutyl, 2-ethylbutyl, hexyl and isohexyl groups; of these, weprefer those alkyl groups having from 1 to 4 carbon atoms, preferablythe methyl, ethyl, propyl, isopropyl, butyl and isobutyl groups, morepreferably the methyl, ethyl, propyl and isopropyl groups, and mostpreferably the methyl group;

alkoxy groups having from 1 to 6 carbon atoms, which may be a straightor branched chain group, and examples include the methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy,isopentyloxy, neopentyloxy, 2-methylbutoxy, 1-ethylpropoxy,4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy,1-methylpentyloxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy,1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy,2,3-dimethylbutoxy, 2-ethylbutoxy, hexyloxy and isohexyloxy groups; ofthese, we prefer those alkoxy groups having from 1 to 4 carbon atoms,preferably the methoxy, ethoxy, propoxy, isopropoxy, butoxy andisobutoxy groups, more preferably the methoxy, ethoxy and propoxygroups, and most preferably the methoxy group;

halgen atoms, such as the fluorine, chlorine, bromine and iodine atoms,particularly the fluorine, chlorine and bromine atoms;

alkoxycarbonyl groups having from 2 to 7 carbon atoms, that is thealkoxy part has from 1 to 6 carbon atoms and may be any of the alkoxygroups defined ande exemplified above; examples of such alkoxycarbonylgroups include the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl,isopentyloxycarbonyl, neopentyloxycarbonyl, 2-methylbutoxycarbonyl,1-ethylpropoxycarbonyl, 4-methylpentyloxycarbonyl,3-methylpentyloxycarbonyl, 2-methylpentyloxycarbonyl,1-methylpentyloxycarbonyl, 3,3-dimethylbutoxycarbonyl,2,2-dimethylbutoxycarbonyl, 1,1-dimethylbutoxycarbonyl,1,2-dimethylbutoxycarbonyl, 1,3-dimethylbutoxycarbonyl,2,3-dimethylbutoxycarbonyl, 2-ethylbutoxycarbonyl, hexyloxycarbonyl andisohexyloxycarbonyl groups; of these, we prefer those alkoxycarbonylgroups having from 1 to 4 carbon atoms, preferably the methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl andisobutoxycarbonyl groups, more preferably the methoxycarbonyl andethoxycarbonyl groups;

groups of formula --CONR^(8') R^(9'), where R^(8') and R^(9') are thesame or different and each represents:

a hydrogen atom, an amino-protecting group (for example as defined andexemplified above in relation to the groups which may be included insubstituents A'), an alkyl group having from 1 to 6 carbon atoms (suchas those exemplified above in relation to substituents C') or a phenylgroup, or R^(8') and R^(9') together represent a group of formula--(CH₂)_(q) '--O_(r) '--(CH₂)_(s) '--, where q' and s' are independentlyselected from the group consisting of 0 and integers of from 1 to 5 andr' is 0 or 1, provided that (q'+s') is an integer of at least 2; and

cyano groups, hydroxy groups and nitro groups.

Where A' represents an aralkyl group, this is as defined above, andexamples include any of the alkyl groups having from 1 to 6, preferablyfrom 1 to 4, carbon atoms exemplified above and substituted by at leastone aryl group, such as those exemplified above. There is no particularlimitation on the number of aryl substituents on the alkyl group, exceptsuch as may be imposed by the number of substitutable positions orpossibly by steric constraints, but, in general, from 1 to 3 aryl groupsare preferred, 2 or 1 being more preferred and 1 being most preferred.The aryl group forming part of the aralkyl group may itself beunsubstituted or it may be substituted by at least one substituentselected from the group consisting of substituents C', defined above andexemplified below. Again, there is no particular limitation on thenumber of substituents on the aryl group, except such as may be imposedby the number of substitutable positions or possibly by stericconstraints, but, in general, from 1 to 5 substituents are preferred,from 1 to 3 being more preferred and 1 being most preferred. Specificexamples of such groups include the benzyl, α-naphthylmethyl,β-naphthylmethyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl,2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 2-methoxybenzyl,3-methoxybenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2-nitrobenzyl,4-nitrobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl,4-bromobenzyl, 4-cyanobenzyl, α or β-naphthylmethyl, benzhydryl (i.e.diphenylmethyl), trityl (i.e. triphenylmethyl), phenethyl,1-phenylethyl, 1-(α or β-naphthyl)ethyl, 2-(α or β-naphthyl)ethyl,1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-(α orβ-naphthyl)propyl, 2-(α or β-naphthyl)propyl, 3-(α or β-naphthyl)propyl,1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1-(α orβ-naphthyl)butyl, 2-(α or β-naphthyl)butyl, 3-(α or β-naphthyl)butyl,4-(α or β-naphthyl)butyl, 1-phenylpentyl, 2-phenylpentyl,3-phenylpentyl, 4-phenylpentyl, 5-phenylpentyl, 1-(α orβ-naphthyl)pentyl, 2-(α or β-naphthyl)pentyl, 3-(α or β-naphthyl)pentyl,4-(α or β-naphthyl)pentyl, 5-(α or β-naphthyl)pentyl, 1-phenylhexyl,2-phenylhexyl, 3-phenylhexyl, 4-phenylhexyl, 5-phenylhexyl,6-phenylhexyl, 1-(α or β-naphthyl)hexyl, 2-(α or β-naphthyl)hexyl, 3-(αor β-naphthyl)hexyl, 4-(α or β-naphthyl)hexyl, 5-(α or β-naphthyl)hexyland 6-(α or β-naphthyl)hexyl groups. Of these, we prefer the benzyl,phenethyl, 3-phenylpropyl and 4-phenylpentyl groups, the unsubstitutedaralkyl groups being more preferred, and the unsubstituted benzyl andphenethyl groups being most preferred.

Where A' represents a heterocyclic group, this has from 3 to 10, morepreferably from 5 to 7, ring atoms in one or more heterocyclic rings, atleast one of said atoms, preferably from 1 to 4 and more preferably from1 to 3 of said atoms, being a hetero-atom selected from the groupconsisting of nitrogen, oxygen and sulfur hetero-atoms, said group beingunsubstituted or being substituted by at least one substituent selectedfrom the group consisting of substituents B' on carbon atoms,substituents B^(1') on nitrogen hetero-atoms, and oxygen atoms to form asulfinyl or sulfonyl group or sulfur hetero-atoms, all as defined andexemplified below, or it may represent a fused heterocyclic group inwhich a heterocyclic group as defined above is fused to an aryl group asdefined above, preferably a phenyl group. The heterocyclic group may bearomatic or non-aromatic, but is preferably non-aromatic. The group maybe a monocyclic group or it may consist of two or more rings attached toeach other by fusion or by a spiro attachment. In the case of thosegroups having 4 hetero-atoms in a ring, we prefer that 3 or 4 of themshould be nitrogen atoms and 1 or 0 should be an oxygen or sulfur atom.In the case of those groups having 3 hetero-atoms in a ring, we preferthat 1, 2 or 3 should be nitrogen atoms and, correspondingly, 2, 1 or 0should be oxygen and/or sulfur atoms. In the case of those groups having1 or 2 hetero-atoms in a ring, the hetero-atoms may be freely chosenfrom nitrogen, oxygen and sulfur atoms. Preferably, however, the groupcontains at least one nitrogen atom. The group may be substituted orunsubstituted and, if substituted, the substituents are selected fromthe group consisting of substituents B', B^(1') and oxygen atoms, asdefined above and exemplified below.

The groups may also be saturated, unsaturated or partially saturatedand, if fully unsaturated, may be aromatic in character. Examples ofsuch non-aromatic groups include the azetidinyl, pyrrolidinyl,oxopyrrolidinyl, piperidyl, oxopiperidyl, morpholinyl (especiallymorpholino), thiomorpholinyl, tetrahydropyrimidinyl, thiazolidinyl,oxazolidinyl, hexahydropyrimidinyl, imidazolidinyl, octahydroazocinyland pyrazolidinyl groups. Of these, we prefer the saturated heterocyclicgroups having 5 or 6 ring atoms and containing at least one nitrogenatom, and optionally an oxygen or sulfur atom or atoms.

These heterocyclyl groups may optionally be condensed with one or moreother cyclic groups such as, for example, the aryl groups and cycloalkylgroups defined and exemplified herein. Examples of such groups include:the 1,2,3,4-tetrahydroisoquinolyl, pyrazolotriazolyldecahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl, decahydroquinolyl,isoindolinyl and indolinyl groups.

Where A' represents a substituted alkyl group, this has from 1 to 6carbon atoms and is substituted by at least one substituent selectedfrom the group consisting of the heterocyclic groups and fusedheterocyclic groups defined and exemplified above.

Such heterocyclic groups and heterocyclic groups which are substituentson alkyl groups represented by A' may be unsubstituted or they may besubstituted by one or more of the following groups and atoms. There isno particular restriction upon the number of substituents which may bepresent, except such as may be imposed by the number of substitutableatoms and possibly by steric constraints. In general, from 1 to 5substituents are preferred, from 1 to 3 being more preferred.

In the case of carbon atoms or sulfur atoms, these may be substituted by1 (carbon atoms) or 1 or 2 (sulfur atoms) oxygen atoms, to form acarbonyl group or a sulfinyl or sulfonyl group.

In the case of carbon atoms, these may be substituted by one or more ofsubstituents B':

alkyl groups having from 1 to 6 carbon atoms, such as the methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl,isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl, 4-methylpentyl,3-methylpentyl, 2-methyl-pentyl, 1-methylpentyl, 3,3-dimethylbutyl,2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, hexyl and isohexylgroups, preferably the methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, t-butyl, pentyl and isopentyl groups;

alkoxy groups having from 1 to 6 carbon atoms, such as the methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy,pentyloxy, isopentyloxy, neopentyloxy, 2-methylbutoxy, 1-ethylpropoxy,4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy,1-methylpentyloxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy,1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy,2,3-dimethylbutoxy, 2-ethylbutoxy, hexyloxy and isohexyloxy groups,preferably the methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,sec-butoxy and t-butoxy groups;

hydroxy groups, cyano groups, nitro groups,

halogen atoms, such as fluorine, chlorine, bromine and iodine atoms;

alkoxycarbonyl groups having from 2 to 7 carbon atoms, such as themethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl,butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl,pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl,2-methylbutoxycarbonyl, 1-ethylpropoxycarbonyl,4-methylpentyloxycarbonyl, 3-methylpentyloxycarbonyl,2-methylpentyloxycarbonyl, 1-methylpentyloxycarbonyl,3,3-dimethylbutoxycarbonyl, 2,2-dimethylbutoxycarbonyl,1,1-dimethylbutoxycarbonyl, 1,2-dimethylbutoxycarbonyl,1,3-dimethylbutoxycarbonyl, 2,3-dimethylbutoxycarbonyl,2-ethylbutoxycarbonyl, hexyloxycarbonyl and isohexyloxycarbonyl groups,preferably the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,sec-butoxycarbonyl and t-butoxycarbonyl groups;

carboxy groups,

cycloalkyl groups having from 3 to 7 ring carbon atoms, preferably 5 or6 ring carbon atoms, such as the cyclopropyl, cyclobutyl, cyclopentyland cyclohexyl groups;

alkoxyalkyl groups in which the alkoxy and alkyl parts both have from 1to 6 carbon atoms, and each may be as defined and exemplified above inrelation to those groups included in substituents B', for example themethoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl,butoxymethyl, 2-methoxyethyl, 3-methoxypropyl, 2-methoxypropyl or4-ethoxybutyl;

alkoxycarbonylalkyl groups in which the alkoxy and alkyl parts both havefrom 1 to 6 carbon atoms, and each may be as defined and exemplifiedabove in relation to those groups included in substituents B', forexample the methoxycarbonylmethyl, ethoxycarbonylmethyl,propoxycarbonylmethyl, isopropoxycarbonylmethyl, butoxycarbonylmethyl,2-methoxycarbonylethyl, 3-methoxycarbonylpropyl, 2-methoxycarbonylpropyland 4-ethoxycarbonylbutyl groups; cyanoalkyl groups in which the alkylpart has from 1 to 6 carbon atoms, such as the cyanomethyl,2-cyanoethyl, 3-cyanopropyl, 2-cyanopropyl and 4-cyanobutyl groups;

haloalkyl groups having from 1 to 6 carbon atoms, in which the alkylpart may be any of those alkyl groups exemplified above and has at leastone halogen substituent; there is no restriction on the number ofhalogen substituents, and the group may be anything from a monohaloalkylgroup to a perhaloalkyl group; preferably there are from 1 to 3 halogenatoms; examples of such groups include the trifluoromethyl,trichloromethyl, fluoromethyl, chloromethyl, bromomethyl, iodomethyl,2-fluoroethyl, 2,2,2-trifluoroethyl, 2-chloroethyl, 2-bromoethyl,3-fluoropropyl, 2-fluoropropyl, 4-chlorobutyl and 3-fluorobutyl groups;

alkanoyloxy groups having from 1 to 6 carbon atoms, such as the acetoxy,propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy,pivaloyloxy and hexanoyloxy groups, preferably the acetoxy,propionyloxy, butyryloxy or isobutyryloxy;

azido groups,

alkylthio groups having from 1 to 6 carbon atoms, such as themethylthio, ethylthio, propylthio, isopropylthio, butylthio,isobutylthio, sec-butylthio, t-butylthio, pentylthio, isopentylthio,neopentylthio, 2-methylbutylthio, 1-ethylpropylthio, 4-methylpentylthio,3-methylpentylthio, 2-methylpentylthio, 1-methylpentylthio,3,3-dimethylbutylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio,1,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,3-dimethylbutylthio,2-ethylbutylthio, hexyl and isohexylthio groups, preferably themethylthio, ethylthio, propylthio, isopropylthio, butylthio andisobutylthio groups;

alkylsulfinyl groups having from 1 to 6 carbon atoms, such as themethylsulfinyl, ethylsulfinyl, propylsulfinyl, isopropylsulfinyl,butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, t-butylsulfinyl,pentylsulfinyl, isopentylsulfinyl, neopentylsulfinyl,2-methylbutylsulfinyl, 1-ethylpropylsulfinyl, 4-methylpentylsulfinyl,3-methylpentylsulfinyl, 2-methylpentylsulfinyl, 1-methylpentylsulfinyl,3,3-dimethylbutylsulfinyl, 2,2-dimethylbutylsulfinyl,1,1-dimethylbutylsulfinyl, 1,2-dimethylbutylsulfinyl,1,3-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl,2-ethylbutylsulfinyl, hexylsulfinyl and isohexylsulfinyl groups,preferably the methylsulfinyl, ethylsulfinyl, propylsulfinyl,isopropylsulfinyl, butylsulfinyl and isobutylsulfinyl groups;

alkylsulfonyl groups having from 1 to 6 carbon atoms, such as themethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl,butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, t-butylsulfonyl,pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl,2-methylbutylsulfonyl, 1-ethylpropylsulfonyl, 4-methylpentylsulfonyl,3-methylpentylsulfonyl, 2-methylpentylsulfonyl, 1-methylpentylsulfonyl,3,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl,1,1-dimethylbutylsulfonyl, 1,2-dimethylbutylsulfonyl,1,3-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl,2-ethylbutylsulfonyl, hexylsulfonyl and isohexylsulfonyl groups,preferably the methylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl and isobutylsulfonyl groups;

groups of formula --NR^(8') R^(9') and groups of formula --CONR^(8')R^(9'), where R^(8') and R^(9') are independently selected from thegroup consisting of hydrogen atoms, amino-protecting groups, alkylgroups having from 1 to 6 carbon atoms and phenyl groups, or R^(8') andR^(9') together represent a group of formula --(CH₂)_(q) '--O_(r)'--(CH₂)_(s) '--, where q' and s' are independently selected from thegroup consisting of 0 and integers of from 1 to 5 and r' is 0 or 1,provided that (q'+s') is an integer of at least 2, all as defined andexemplified above; and

groups of formulae (B-I'), (B-II'), (B-III'), (B-IV'), (B-V'), (B-VI'),(B-VII'), (B-VIII') and (B-IX'), as shown above.

In formulae (B-I') to (B-IX'):

R^(20') represents a hydrogen atom, an amino-protecting group (such asthose exemplified above in relation to A'), a group of formula--COR^(26'), where

R^(26') represents an alkyl group having from 1 to 6 carbon atoms (suchas those exemplified above in relation to R^(1'), preferably a methylgroup), or a substituted alkyl group which has from 1 to 6 carbon atomsand which is substituted by at least one substituent selected from thegroup consisting of substituents A';

a group of formula --C(═NR^(16'))R^(17'), where

R^(16') and R^(17') are independently selected from the group consistingof hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms (such asthose exemplified above in relation to R^(1'), preferably a methylgroup), amino groups, protected amino groups (such as those exemplifiedabove in relation to A') and amino-protecting groups (such as thoseexemplified above in relation to A');

an unsubstituted alkyl group having from 1 to 6 carbon atoms (such asthose exemplified above in relation to R^(1'), preferably a methylgroup), or a substituted alkyl group which has from 1 to 6 carbon atomsand which is substituted by at least one substituent selected from thegroup consisting of substituents D, defined and exemplified below.

R^(21') and R^(22') are independently selected from the group consistingof hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms (such asthose exemplified above in relation to R^(1'), preferably a methylgroup), hydroxy groups and protected hydroxy groups (such as thosedefined and exemplified above in relation to R^(6'));

R^(28') and R^(29') are independently selected from the group consistingof hydrogen atoms, alkyl groups having from 1 to 6 carbon atoms (such asthose exemplified above in relation to R^(1'), preferably a methylgroup), amino-protecting (such as those exemplified above in relation toA') groups, amino groups, protected amino groups (such as thoseexemplified above in relation to A') and groups of formula--C(═NR^(16'))R^(17'), where R^(16') and R^(17') are as defined above.

R^(30') represents a hydrogen atom, an alkyl group having from 1 to 6carbon atoms (such as those exemplified above in relation to R^(1'),preferably a methyl group) or a substituted alkyl group which has from 1to 6 carbon atoms and which is substituted by at least one substituentselected from the group consisting of hydroxy groups (for example a1-hydroxyethyl group) and protected hydroxy groups (such as thosedefined and exemplified above in relation to R^(6')).

R^(31') represents a hydrogen atom, an alkyl group having from 1 to 6carbon atoms (such as those exemplified above in relation to R^(1'),preferably a methyl group) or an amino-protecting group (such as thoseexemplified above in relation to A').

R^(32') represents a hydrogen atom, an alkyl group having from 1 to 6carbon atoms (such as those exemplified above in relation to R^(1'),preferably a methyl group) or a group of formula --NR^(28') R^(29'), inwhich R^(28') and R^(29') are as defined above.

E' represents an imidazolyl group or a triazolyl group.

W' represents an aromatic heterocyclic group having from 5 to 8,preferably 5 or 6, ring atoms, of which from 1 to 4 are nitrogen atoms,said aromatic heterocyclic group being unsubstituted or beingsubstituted by at least one alkyl group having from 1 to 6 carbon atoms(such as those exemplified above in relation to R^(1'), preferably amethyl group); specific examples of such aromatic heterocyclic groupsinclude the pyridyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl,triazolyl and tetrazolyl groups.

Where there is, as is preferred, a nitrogen atom in the heterocyclicgroup, this may also be substituted, and the substituents are selectedfrom the group consisting of substituents B^(1'), which include:

alkyl groups having from 1 to 6 carbon atoms, such as those exemplifiedabove in relation to R^(1'), preferably a methyl group; groups offormula --C(═NR^(16'))R^(17'), where R^(16') and R^(17') are as definedand exemplified above;

amino-protecting groups, such as those exemplified above in relation toA'; and

groups of formula --CONR^(18') R^(19'), where

R^(18') and R^(19') are independently selected from the group consistingof alkyl groups having from 1 to 6 carbon atoms (such as thoseexemplified above in relation to R^(1'), preferably a methyl, ethyl,propyl or isopropyl group) and carboxylic acyl groups (preferablyoxycarbonyl groups, as defined and exemplified above in relation to theoxycarbonyl groups which may be represented by R^(6').

Substituents D' are selected from the group consisting of hydroxygroups, protected hydroxy groups (such as those defined and exemplifiedabove in relation to R^(6')), carboxy groups, protected carboxy groups(such as those defined and exemplified above in relation to R^(1')),cyano groups, alkoxy groups having from 1 to 6 carbon atoms (such asthose defined and exemplified above in relation to R^(7'), preferably amethoxy group), alkylsulfonyl groups having from 1 to 6 carbon atoms(such as those exemplified above in relation to substituents B), andgroups of formula --NHCOR^(23'), --NR^(24') R^(25'), --CONR^(24')R^(25') or --OCONR^(24') R^(25'), where R^(23'), R^(24') and R^(25') areindependently selected from the group consisting of hydrogen atoms andalkyl groups having from 1 to 6 carbon atoms (such as those exemplifiedabove in relation to R^(1'), preferably a methyl, ethyl, propyl orisopropyl group).

Where R^(4') represents an alkyl group, this may be as defined andexemplified above. The group may be unsubstituted or it may besubstituted by one or more substituents selected from the groupconsisting of substituents E', which include: hydroxy groups, protectedhydroxy groups (such as those defined and exemplified above in relationto R^(6')), amino groups and protected amino groups (such as thoseexemplified above in relation to A').

Where R^(4') represents an alkenyl group, this has from 2 to 6,preferably 3 or 4, carbon atoms and is unsubstituted or is substitutedby at least one substituent selected from the group consisting ofsubstituents E', defined and exemplified above. Examples include thevinyl, allyl, methallyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl,3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl and 4-pentenyl groups, ofwhich the vinyl, allyl, 1-propenyl, and 1-butenyl groups are preferred,the vinyl, allyl and 1-butenyl groups being most preferred.

Where R^(4') represents an aryl or aralkyl group, this may be any one ofthe aryl or aralkyl groups defined and exemplified above in relation toA', and, as with A', it may be substituted or unsubstituted.

Where R^(4') represents a cycloalkyl group, this has from 3 to 7 carbonatoms and is unsubstituted or is substituted by at least one substituentselected from the group consisting of substituents C', defined andexemplified above. Preferred cycloalkyl groups have from 4 to 6 carbonatoms, and examples of such groups include the cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl groups, of which the cyclobutyl,cyclopentyl and cyclohexyl groups are preferred.

Where R^(4') represents an aromatic heterocyclic group, this has from 5to 7, preferably 5 or 6, ring atoms in an aromatic heterocyclic ring,and this may optionally be fused to an aryl group, as defined andexemplified above, preferably a phenyl group. It has at least onehetero-atom selected from the group consisting of nitrogen, oxygen andsulfur hetero-atoms, and preferably has from 1 to 4, more preferablyfrom 1 to 3 and most preferably 1 or 2, such hetero-atoms. In the caseof those groups having 4 hetero-atoms in a ring, we prefer that 3 or 4of them should be nitrogen atoms and 1 or 0 should be an oxygen orsulfur atom. In the case of those groups having 3 hetero-atoms in aring, we prefer that 1, 2 or 3 should be nitrogen atoms and,correspondingly, 2, 1 or 0 should be oxygen and/or sulfur atoms. In thecase of those groups having 1 or 2 hetero-atoms in a ring, thehetero-atoms may be freely chosen from nitrogen, oxygen and sulfuratoms. Preferably, however, the group contains at least one nitrogenatom. Examples of such aromatic heterocyclic groups include the2-pyridyl, 3-pyridyl, 2-pyrimidinyl, 2-imidazolyl, 3-thiazolyl,2-thienyl and 2-furyl groups. These groups may be unsubstituted or theymay have one or more substituents selected from the group consisting ofsubstituents C', defined and exemplified above.

Where R^(4') represents an alkyl group which has from 1 to 6 carbonatoms and which is substituted by at least one substituent selected fromthe group consisting of aromatic heterocylic groups and fusedheterocyclic groups, the heterocyclic groups may be as defined andexemplified above; and the alkyl groups may be any of the alkyl groupshaving from 1 to 6, preferably from 1 to 4 and more preferably 1, 2 or3, carbon atoms defined and exemplified above in relation to R^(2')etc., the methyl and ethyl groups being most preferred.

In the compounds of formula (IV'), R^(1') may be the same as in thecompounds of formula (I') and (II'). In these compounds, particularlypreferred groups are the:

alkyl groups, especially the methyl, ethyl and t-butyl groups,

aralkyl groups, especially the benzyl, benzhydryl, 4-nitrobenzyl and2-nitrobenzyl groups,

alkenyl groups, especially the allyl, 2-chloroallyl and 2-methylallylgroups,

haloalkyl groups, especially the 2,2,2-trichloroethyl and2,2,2-tribromoethyl groups, and

the 2-trimethylsilylethyl group.

Also, R^(41') may be a hydrogen atom or a hydroxy-protecting group,which latter may be any of the groups defined and exemplified above inrelation to R^(6'). Particularly preferred such groups in the case ofR^(41') are:

tri-substituted silyl groups, such as those previously exemplified,particularly the t-butyldimethylsilyl, t-butyldiphenylsilyl,trimethylsilyl and triethylsilyl groups;

aralkyloxycarbonyl groups, such as those defined and exemplified above,preferably the benzyloxycarbonyl and 4-nitrobenzyloxycarbonyl groups;and

unsubstituted and substituted acetyl groups, particularly those in whichthe substituents are selected from the group consisting of substituentsC', defined and exemplified above, and especially the acetyl,chloroacetyl and methoxyacetyl groups.

R^(42'), R^(43'), R^(45') and R^(46') may represent an alkyl grouphaving from 1 to 6 carbon atoms, which may be as defined and exemplifiedabove in relation to R^(2') and R^(3'). Particularly preferred suchgroups are the methyl, ethyl, propyl, isobutyl, pentyl and hexyl groups,of which the methyl, ethyl and propyl groups are most preferred.

R^(42') and R^(43') may represent an alkoxy group having from 1 to 6carbon atoms, which may be as defined and exemplified above in relationto R^(7'). Particularly preferred such groups are the methoxy, ethoxy,propoxy, isobutoxy, pentyloxy and hexyloxy groups, of which the methoxy,ethoxy and propoxy groups are most preferred.

R^(42') and R^(43') may represent a halogen atom, for example afluorine, chlorine, bromine or iodine atom, of which the fluorine,chlorine and bromine atoms are preferred and the fluorine and chlorineatoms are more preferred.

R^(42'), R^(45') and R^(46') may represent an aryl group, which may beas defined and exemplified above in relation to R^(4'). A particularlypreferred such group is the phenyl group. Where R^(42') represents anaryloxy group, this may be the aryloxy equivalent of any of the arylgroups defined and exemplified above in relation to R^(4'). Aparticularly preferred such group is the phenoxy group.

Preferred compounds of formula (I') are those in which:

(1) R^(1') represents:

a hydrogen atom,

an alkyl group having from 1 to 6 carbon atoms,

an aralkyl group which is an alkyl group having from 1 to 4 carbon atomsand which is substituted by at least one aryl group, as defined above,

an alkenyl group having from 2 to 6 carbon atoms, and which isunsubstituted or is substituted by one or more halogen atoms,

a haloalkyl group having from 1 to 6 carbon atoms,

a tri-substituted silylethyl group, in which all three or two or one ofthe substituents are alkyl groups having from 1 to 5 carbon atoms, andnone, one or two of the substituents are aryl groups, as defined above,

an acyloxyalkyl group, in which the acyl part is an alkanoyl grouphaving from 1 to 6 carbon atoms and the alkyl part has from 1 to 6carbon atoms,

an alkoxycarbonyloxyalkyl group in which the alkoxy and alkyl parts eachhave from 1 to 6 carbon atoms,

a cycloalkoxycarbonyloxyalkyl groups in which the cycloalkyl part hasfrom 3 to 7 ring carbon atoms and may be unsubstituted or substituted byat least one substituent selected from the group consisting ofsubstituents C', defined above and the alkyl part has from 1 to 6 carbonatoms

a (5-alkyl or 5-aryl -2-oxo-1,3-dioxolen-4-yl)methyl group in which thealkyl part has from 1 to 4 carbon atoms and the aryl part is as definedabove; or

the 3-phthalidyl group;

(2) R^(2') and R^(3') are independently selected from the groupconsisting of hydrogen atoms, alkyl groups having from 1 to 4 carbonatoms and groups of formula ##STR26## where R^(5') represents a hydrogenatom or a methyl group; and R^(6') represents:

a hydrogen atom,

a substituted silyl group, in which the silyl group has 3 substituentsselected from alkyl groups having from 1 to 6 carbon atoms and phenylgroups,

an aralkyl group, in which an alkyl group having from 1 to 4 carbonatoms is substituted by at least one aryl group, as defined above,

an aralkyloxycarbonyl group, in which the aralkyl part is as definedabove,

an alkenyloxycarbonyl group in which the alkenyl part has from 2 to 6carbon atoms and is unsubstituted or is substituted by at least onehalogen atom,

an alkoxycarbonyl group which has from 2 to 7 carbon atoms,

a substituted silylalkoxycarbonyl group, in which the alkoxycarbonylpart and the substituted silyl part are as defined above,

an oxygen-containing heterocyclic group,

an alkoxyalkyl group in which the alkoxy and alkyl parts each have from1 to 6 carbon atoms,

a substituted silylalkoxyalkyl group, in which the alkoxyalkyl part andthe substituted silyl part are as defined above, or

an alkanoyl or haloalkanoyl group which has no more than 6 carbon atoms;or

R^(2') and R^(3') together represent a group of formula ═C(CH₃)CH₂OR^(6'), in which R^(6') is as defined above;

(3) X' represents a sulfur atom or a group of formula >CHR^(7'), whereR^(7') represents a hydrogen atom, an alkyl group having from 1 to 4carbon atoms or an alkoxy group having from 1 to 4 carbon atoms; and

(4) A' represents

an alkyl group which has from 1 to 4 carbon atoms and which isunsubstituted or is substituted by 1 or 2 substituents selected from thegroup consisting of substituents A^(a'), defined below,

an aryl group, as defined below,

an aralkyl group in which an alkyl group having from 1 to 3 carbon atomsis substituted by at least one aryl group as defined below,

a heterocylic group which has from 4 to 7 ring atoms, at least one ofsaid atoms being a hetero-atom selected from the group consisting ofnitrogen, oxygen and sulfur hetero-atoms, said group being unsubstitutedor being substituted by at least one substituent selected from the groupconsisting of substituents B^(a') on carbon atoms, substituents B^(a1')on nitrogen hetero-atoms, and oxygen atoms to form a sulfinyl orsulfonyl group on sulfur hetero-atoms, all as defined below;

an alkyl group which has from 1 to 3 carbon atoms and which issubstituted by at least one substituent selected from the groupconsisting of the heterocyclic groups defined above;

said aryl groups are aromatic carbocyclic groups having from 6 to 10ring carbon atoms and are unsubstituted or are substituted by at leastone substituent selected from the group consisting of substituentsC^(a'), defined below;

said substituents A^(a') are selected from the group consisting ofhydroxy groups, protected hydroxy groups, amino groups, protected aminogroups, groups of formula --C(═NR^(10'))NR^(11') R^(12'), where

R^(10'), R^(11') and R^(12') are independently selected from the groupconsisting of hydrogen atoms, amino-protecting groups and alkyl groupshaving from 1 to 4 carbon atoms, or R^(11') and R^(12') togetherrepresent a group of formula --(CH₂)_(n') --, where n is an integer from2 to 6, or R^(10') and R^(11') together represent a group of formula--(CH₂)_(p') --, where p' is 2 or 3, and

groups of formula --NR^(13') C(═NR^(14'))R^(15'), where

R^(13') and R^(14') are independently selected from the group consistingof hydrogen atoms, amino-protecting groups and alkyl groups having from1 to 6 carbon atoms, and

R^(15') represents a hydrogen atom, an alkyl group having from 1 to 4carbon atoms, an amino group or a protected amino group, or

any two of R^(13'), R^(14') and R^(15') together represent a group offormula --(CH₂)_(p') --, where p' is 2 or 3;

said substituents B^(a') are selected from the group consisting of

alkyl groups having from 1 to 4 carbon atoms,

alkoxy groups having from 1 to 6 carbon atoms,

hydroxy groups,

halogen atoms,

cyano groups,

nitro groups,

alkoxycarbonyl groups having from 2 to 5 carbon atoms,

carboxy groups,

oxygen atoms, to form with a ring carbon atom a carbonyl group,

alkoxyalkyl groups in which the alkoxy and alkyl parts both have from 1to 6 carbon atoms,

haloalkyl groups having from 1 to 6 carbon atoms,

alkanoyloxy groups having from 1 to 6 carbon atoms,

groups of formula --NR^(8') R^(9') and groups of formula --CONR^(8')R^(9'), where R^(8') and R^(9') are independently selected from thegroup consisting of hydrogen atoms, amino-protecting groups, alkylgroups having from 1 to 4 carbon atoms and phenyl groups, or R^(8') andR^(9') together represent a group of formula --(CH₂)_(q') --O_(r')--(CH₂)_(s') --, where q' and s' are independently selected from thegroup consisting of 0 and integers of from 1 to 5 and r' is 0 or 1,provided that (q'+s') is an integer of at least 2; and

groups of formulae (B-I'), (B-II'), (B-III'), (B-IV'), (B-V'), (B-VI'),(B-VII'), (B-VIII') and (B-IX') as defined above;

said substituents B^(a1') are selected from the group consisting ofalkyl groups having from 1 to 4 carbon atoms, amino-protecting groups,groups of formula --C(═NR^(16'))R^(17'), where R^(16') and R^(17') areas defined above, amino-protecting groups and groups of formula--CONR^(18') R^(19'), where

R^(18') and R^(19') are independently selected from the group consistingof alkyl groups having from 1 to 4 carbon atoms, alkanoyl groups havingfrom 2 to 5 carbon atoms and benzoyl groups;

said substituents C' are selected from the group consisting of alkylgroups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4carbon atoms, halogen atoms, alkoxycarbonyl groups having from 2 to 5carbon atoms, groups of formula --CONR^(8') R^(9'), where R^(8') andR^(9') are as defined above, cyano groups, hydroxy groups and nitrogroups.

More preferred compounds of formulae (I') and (II') of the presentinvention are those compounds in which:

(5) R^(1') represents:

a hydrogen atom,

an alkyl group having from 1 to 4 carbon atoms,

an aralkyl group which is an alkyl group having 1 or 2 carbon atoms andwhich is substituted by at least one phenyl group

a haloalkyl group having from 1 to 4 carbon atoms,

a tri-substituted silylethyl group, in which all three or two of thesubstituents are alkyl groups having from 1 to 4 carbon atoms, and noneor one of the substituents are phenyl groups,

an acyloxyalkyl group, in which the acyl part is an alkanoyl grouphaving from 2 to 5 carbon atoms and the alkyl part has 1 or 2 carbonatoms,

an alkoxycarbonyloxyalkyl group in which the alkoxy and alkyl parts eachhave from 1 to 4 carbon atoms,

a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group, or

a 3-phthalidyl group;

(6) R^(2') and R^(3') are independently selected from the groupconsisting of hydrogen atoms, alkyl groups having from 1 to 4 carbonatoms and groups of formula ##STR27## where R^(5') represents a hydrogenatom or a methyl group; and R^(6') represents:

a hydrogen atom,

a substituted silyl group, in which the silyl group has 3 substituentsselected from alkyl groups having from 1 to 4 carbon atoms and phenylgroups,

an aralkyl group, in which an alkyl group having from 1 to 4 carbonatoms is substituted by at least one aryl group, as defined above,

an alkoxycarbonyl group which has from 2 to 7 carbon atoms,

a tetrahydropyranyl group,

an alkoxyalkyl group in which the alkoxy and alkyl parts each have from1 to 4 carbon atoms,

an alkanoyl or haloalkanoyl group which has from 2 to 5 carbon atoms; or

R^(2') and R^(3') together represent a group of formula ═C(CH₃)CH₂OR^(6'), in which R^(6') is as defined above;

(7) X' represents a sulfur atom or a group of formula >CHR^(7'), whereR^(7') represents a hydrogen atom, an alkyl group having 1 or 2 carbonatoms or an alkoxy group having 1 or 2 carbon atoms; and

(8) A' represents

an alkyl group which has 1 or 2 carbon atoms and which is unsubstitutedor is substituted by 1 or 2 substituents selected from the groupconsisting of substituents A^(b'), defined below,

a phenyl group, which is unsubstituted or is substituted by 1 or 2substituents selected from the group consisting of substituents C^(b'),defined below,

an aralkyl group in which an alkyl group having from 1 to 3 carbon atomsis substituted by at least one phenyl group, which is unsubstituted oris substituted by 1 or 2 substituents selected from the group consistingof substituents C^(b'), defined below,

a heterocylic group which has 5 or 6 ring atoms, from 1 to 3 of saidatoms being a hetero-atom selected from the group consisting ofnitrogen, oxygen and sulfur hetero-atoms, said group being unsubstitutedor being substituted by at least one substituent selected from the groupconsisting of substituents B^(b') on carbon atoms, substituents B^(b1')on nitrogen hetero-atoms, and oxygen atoms to form a sulfinyl orsulfonyl group on sulfur hetero-atoms, all as defined below;

said substituents A^(b') are selected from the group consisting ofhydroxy groups, protected hydroxy groups, amino groups and protectedamino groups;

said substituents B^(b') are selected from the group consisting of

alkyl groups having 1 or 2 carbon atoms,

alkoxy groups having 1 or 2 carbon atoms,

hydroxy groups,

halogen atoms,

cyano groups,

nitro groups,

alkoxycarbonyl groups having from 2 to 5 carbon atoms,

carboxy groups,

haloalkyl groups having from 1 to 6 carbon atoms,

alkanoyloxy groups having from 1 to 6 carbon atoms,

groups of formula --NR^(8') R^(9') and groups of formula --CONR^(8')R^(9'), where R^(8') and R^(9') are independently selected from thegroup consisting of hydrogen atoms, amino-protecting groups, alkylgroups having 1 or 2 carbon atoms and phenyl groups, or R^(8') andR^(9') together represent a group of formula --(CH₂)_(q') --O_(r')--(CH₂)_(s') --, where q' and s' are independently selected from thegroup consisting of 0 and integers of from 1 to 5 and r' is 0 or 1,provided that (q'+s') is an integer of at least 2; and groups offormulae (B-I'), (B-II'), (B-III'), (B-IV'), (B-V'), (B-VI'), (B-VII'),(B-VIII') and (B-IX') as defined above;

said substituents B^(b1') are selected from the group consisting ofalkyl groups having 1 or 2 carbon atoms, amino-protecting groups, groupsof formula --C(═NR^(16'))R^(17'), where R^(16') and R^(17') are asdefined above, amino-protecting groups and groups of formula--CONR^(18') R^(19'), where

R^(18') and R^(19') are independently selected from the group consistingof alkyl groups having 1 or 2 carbon atoms, alkanoyl groups having from2 to 5 carbon atoms and benzoyl groups;

said substituents C^(b') are selected from the group consisting of alkylgroups having 1 or 2 carbon atoms, alkoxy groups having 1 or 2 carbonatoms, halogen atoms, groups of formula --CONR^(8') R^(9'), where R^(8')and R^(9') are as defined above, cyano groups, hydroxy groups and nitrogroups.

Preferred compounds of formula (IV') of the present invention are thosecompounds in which:

(9) R^(1') represents:

a hydrogen atom,

an alkyl group having from 1 to 6 carbon atoms,

an aralkyl group which is an alkyl group having from 1 to 4 carbon atomsand which is substituted by at least one aryl group, as defined above,

an alkenyl group having from 2 to 6 carbon atoms, and which isunsubstituted or is substituted by one or more halogen atoms,

a haloalkyl group having from 1 to 6 carbon atoms,

a tri-substituted silylethyl group, in which all three or two or one ofthe substituents are alkyl groups having from 1 to 5 carbon atoms, andnone, one or two of the substituents are aryl groups, as defined above,

an acyloxyalkyl group, in which the acyl part is an alkanoyl grouphaving from 1 to 6 carbon atoms and the alkyl part has from 1 to 6carbon atoms,

an alkoxycarbonyloxyalkyl group in which the alkoxy and alkyl parts eachhave from 1 to 6 carbon atoms,

a cycloalkoxycarbonyloxyalkyl groups in which the cycloalkyl part hasfrom 3 to 7 ring carbon atoms and may be unsubstituted or substituted byat least one substituent selected from the group consisting ofsubstituents C', defined above and alkyl part has from 1 to 6 carbonatoms,

a (5-alkyl or 5-aryl -2-oxo-1,3-dioxolen-4-yl)methyl group in which thealkyl part has from 1 to 4 carbon atoms and the aryl part is as definedabove; or

the 3-phthalidyl group;

(10) R^(41') represents:

a hydrogen atom,

a substituted silyl group, in which the silyl group has 3 substituentsselected from alkyl groups having from 1 to 6 carbon atoms and phenylgroups,

an aralkyl group, in which an alkyl group having from 1 to 4 carbonatoms is substituted by at least one aryl group, as defined above,

an aralkyloxycarbonyl group, in which the aralkyl part is as definedabove,

an alkenyloxycarbonyl group in which the alkenyl part has from 2 to 6carbon atoms and is unsubstituted or is substituted by at least onehalogen atom,

an alkoxycarbonyl group which has from 2 to 7 carbon atoms,

a substituted silylalkoxycarbonyl group, in which the alkoxycarbonylpart and the substituted silyl part are as defined above,

an oxygen-containing heterocyclic group,

an alkoxyalkyl group in which the alkoxy and alkyl parts each have from1 to 6 carbon atoms,

a substituted silylalkoxyalkyl group, in which the alkoxyalkyl part andthe substituted silyl part are as defined above, or

an alkanoyl or haloalkanoyl group which has no more than 6 carbon atoms;

(11) R^(42') represents an alkyl group having from 1 to 4 carbon atoms,an alkoxy group having from 1 to 4 carbon atoms, a halogen atom, an arylgroup as defined below or an aryloxy group in which the aryl part is asdefined below;

(12) R^(43') represents a hydrogen atom, an alkyl group having from 1 to4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, ahydroxy group, a halogen atom, a cyano group, a nitro group or a groupof formula --NR^(8') R^(9'), where R^(8') and R^(9') are independentlyselected from the group consisting of hydrogen atoms, amino-protectinggroups, alkyl groups having from 1 to 4 carbon atoms and phenyl groups,or R^(8') and R^(9') together represent a group of formula --(CH₂)_(q')--O_(r') --(CH₂)_(s') --, where q' and s are independently selected fromthe group consisting of 0 and integers of from 1 to 5 and r' is 0 or 1,provided that (q'+s') is an integer of at least 2; and

(13) R^(45') and R^(46') are independently selected from the groupconsisting of alkyl groups having from 1 to 4 carbon atoms and arylgroups as defined below, or R^(45') and R^(46') together represent agroup of formula --(CH₂)_(q') --O_(r') --(CH₂)_(s') --, where

q' and s' are independently selected from the group consisting of 0 andintegers of from 1 to 5 and r' is 0 or 1.

More preferred compounds of formula (IV') are those in which:

(14) R^(1') represents:

a hydrogen atom;

an alkyl group having from 1 to 4 carbon atoms,

an aralkyl group which is an alkyl group having 1 or 2 carbon atoms andwhich is substituted by at least one phenyl group,

a haloalkyl group having from 1 to 4 carbon atoms,

a tri-substituted silylethyl group, in which all three or two of thesubstituents are alkyl groups having from 1 to 4 carbon atoms, and noneor one of the substituents are phenyl groups,

an acyloxyalkyl group, in which the acyl part is an alkanoyl grouphaving from 2 to 5 carbon atoms and the alkyl part has 1 or 2 carbonatoms,

an alkoxycarbonyloxyalkyl group in which the alkoxy and alkyl parts eachhave from 1 to 4 carbon atoms,

a (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl group, or

a 3-phthalidyl group;

said aryl groups are aromatic carbocyclic groups having from 6 to 10ring carbon atoms and are unsubstituted or are substituted by at leastone substituent selected from the group consisting of substituentsC^(a'), defined above;

(15) R^(41') represents:

a hydrogen atom,

a substituted silyl group, in which the silyl group has 3 substituentsselected from alkyl groups having from 1 to 4 carbon atoms and phenylgroups,

an aralkyl group, in which an alkyl group having 1 or 2 carbon atoms issubstituted by at least one aryl group, as defined above,

an aralkyloxycarbonyl group, in which the aralkyl part is as definedabove,

an alkoxycarbonyl group which has from 2 to 5 carbon atoms,

a tetrahydropyranyl group,

an alkoxyalkyl group in which the alkoxy and alkyl parts each have from1 to 4 carbon atoms,

an alkanoyl or haloalkanoyl group which has from 2 to 5 carbon atoms;

(16) R^(42') represents an alkyl group having 1 or 2 carbon atoms, analkoxy group having 1 or 2 carbon atoms, a halogen atom, a phenyl groupor a phenoxy group;

(17) R^(43') represents a hydrogen atom, an alkyl group having 1 or 2carbon atoms, an alkoxy group having 1 or 2 carbon atoms, a hydroxygroup, a halogen atom, a cyano group, a nitro group or a group offormula --NR^(8') R^(9'), where R^(8') and R^(9') are independentlyselected from the group consisting of hydrogen atoms, amino-protectinggroups, alkyl groups having 1 or 2 carbon atoms and phenyl groups, orR^(8') and R^(9') together represent a group of formula --(CH₂)_(q')--O_(4') --(CH₂)_(s') --, where q' and s' are independently selectedfrom the group consisting of 0 and integers of from 1 to 5 and r' is 0or 1, provided that (q'+s') is an integer of at least 2; and

(18) R^(45') and R^(46') are independently selected from the groupconsisting of alkyl groups having 1 or 2 carbon atoms and phenyl groups,or R^(45') and R^(46') together represent a group of formula--(CH₂)_(q') --O_(r') --(CH₂)_(s') --, where

q' and s' are independently selected from the group consisting of 0 andintegers of from 1 to 5 and r' is 0 or 1.

Specific examples of compounds of formulae (I') and (II') are given inthe following Tables 4 and 5, and specific examples of compounds offormula (IV') of the present invention are shown in formulae (I-3') and(I-4'), in which the substituents are as shown in the respective one ofthe following Tables 6 and 7, that is Table 6 relates to formula (I-3')and Table 7 relates to formula (I-4'). Preferred compounds of thepresent invention are those having the configuration shown in formulae(I-3a') and (Io4a'). Certain of the groups represented by R^(4') areshown by the following formulae (1-1') to (1-30'). ##STR28##

In the Tables 4 to 7, the following abbreviations are used:

    ______________________________________                                        Ac            acetyl                                                          All           allyl                                                           Azp           perhydroazepinyl                                                Bu            butyl                                                           iBu           isobutyl                                                        Bz            benzyl                                                          Et            ethyl                                                           Imid          imidazolyl                                                      Ithiz         isothiazolyl                                                    Me            methyl                                                          Ph            phenyl                                                          Piz           piperazinyl                                                     PNB           4-nitrobenzyl                                                   PNZ           4-nitrobenzyloxycarbonyl                                        Pr            propyl                                                          iPr           isopropyl                                                       Pyr           pyridyl                                                         Pyrd          pyrrolidinyl                                                    Pyrz          pyrazolidinyl                                                   TBS           t-butyldimethylsilyl                                            Tht           1-oxotetrahydrothien-3-yl                                       TMS           trimethylsilyl                                                  G             hydrogen, TMS, TBS, or PNZ                                      ______________________________________                                    

                                      TABLE 4                                     __________________________________________________________________________    Cpd.                                                                          No.                                                                              R.sup.1'                                                                         R.sup.2'                                                                        R.sup.3'                                                                             R.sup.4'           X'                                          __________________________________________________________________________    1-1'                                                                             PNB                                                                              H 1-(G--O)Et                                                                           1-PNZ-5-Me.sub.2 NCO-3-Pyrd                                                                      >CH(CH.sub.3)                               1-2'                                                                             PNB                                                                              H 1-(G--O)Et                                                                           --CH.sub.2 CH.sub.2 NH.PNZ                                                                       >CH(CH.sub.3)                               1-3'                                                                             PNB                                                                              H 1-(G--O)Et                                                                           4-NO.sub.2 Bz      >CH(CH.sub.3)                               1-4'                                                                             PNB                                                                              H 1-(G--O)Et                                                                           Ph                 >CH(CH.sub.3)                               1-5'                                                                             PNB                                                                              H 1-(G--O)Et                                                                           1-[1-(PNZ.N═)Et]-3-Pyrd                                                                      >CH(CH.sub.3)                               1-6'                                                                             PNB                                                                              H 1-(G--O)Et                                                                           2-[1-Azp.CO]Ph     >CH(CH.sub.3)                               1-7'                                                                             PNB                                                                              H 1-(G--O)Et                                                                           1-PNZ-5-[4-(2-PNZ.OEt)PizCO]Pyrd                                                                 >CH(CH.sub.3)                               1-8'                                                                             PNB                                                                              H 1-(G--O)Et                                                                           --CH.sub.2 --C(NMe.sub.2)═N.PNZ                                                              >CH(CH.sub.3)                               1-9'                                                                             PNB                                                                              H 1-(G--O)Et                                                                           1,2-di(PNZ)-4-Pyrz >CH(CH.sub.3)                               1-10'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           formula (1-1')     >CH(CH.sub.3)                               1-11'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           formula (1-2')     >CH(CH.sub.3)                               1-12'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           formula (1-3')     >CH(CH.sub.3)                               1-13'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           1-PNZ-5-PhSCO-3-Pyrd                                                                             >CH(CH.sub.3)                               1-14'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           5-oxo-2-Pyrd       >CH(CH.sub.3)                               1-15'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           5-oxo-3-Pyrid      >CH(CH.sub.3)                               1-16'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           2-oxo-3-Pip        >CH(CH.sub.3)                               1-17'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           formula (1-4')     >CH(CH.sub.3)                               1-18'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           formula (1-5')     >CH(CH.sub.3)                               1-19'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           formula (1-6')     >CH(CH.sub.3)                               1-20'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           formula (1-7')     >CH(CH.sub.3)                               1-21'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           formula (1-8')     >CH(CH.sub.3)                               1-22'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           1-PNZ-5-[4-(2-HOEt)-1-PizCO]-3-Pyrd                                                              >CH(CH.sub.3)                               1-23'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           formula (1-9')     >CH(CH.sub.3)                               1-24'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           formula (1-10')    >CH(CH.sub.3)                               1-25'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           formula (1-11')    >CH(CH.sub.3)                               1-26'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           formula (1-12')    >CH(CH.sub.3)                               1-27'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           formula (1-13')    >CH(CH.sub.3)                               1-28'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           formula (1-14')    >CH(CH.sub.3)                               1-29'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           formula (1-15')    >CH(CH.sub.3)                               1-30'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           formula (1-16')    >CH(CH.sub.3)                               1-31'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           formula (1-17')    >CH(CH.sub.3)                               1-32'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           formula (1-18')    >CH(CH.sub.3)                               1-33'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           formula (1-19')    >CH(CH.sub.3)                               1-34'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           formula (1-20')    >CH(CH.sub.3)                               1-35'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           formula (1-21')    >CH(CH.sub.3)                               1-36'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           formula (1-22')    >CH(CH.sub.3)                               1-37'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           formula (1-23')    >CH(CH.sub.3)                               1-38'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           formula (1-24')    >CH(CH.sub.3)                               1-39'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           formula (1-25')    >CH(CH.sub.3)                               1-40'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           formula (1-26')    >CH(CH.sub.3)                               1-41'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           formula (1-27')    >CH(CH.sub.3)                               1-42'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           formula (1-28')    >CH(CH.sub.3)                               1-43'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           1-[1-(PNZ.N═Et]-3-Pyrd                                                                       >CH.sub.2                                   1-44'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           2-(PNZ--N═CH--NH)Et                                                                          >CH.sub.2                                   1-45'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           --CH.sub.2 CH.sub.2 NH.PNZ                                                                       >CH.sub.2                                   1-46'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           1-PNZ-5-Me.sub.2 NCO-3-Pyrd                                                                      >CH.sub.2                                   1-47'                                                                            All                                                                              H 1-(G--O)Et                                                                           1-PNZ-5-Me.sub.2 NCO-3-Pyrd                                                                      >CH(CH.sub.3)                               1-48'                                                                            All                                                                              H 1-(G--O)Et                                                                           formula (1-11)     >CH(CH.sub.3)                               1-49'                                                                            All                                                                              H 1-(G--O)Et                                                                           2-oxo-3-Pip        >CH(CH.sub.3)                               1-50'                                                                            All                                                                              H 1-(G--O)Et                                                                           5-oxo-3-Pyrd       >CH(CH.sub.3)                               1-51'                                                                            PNB                                                                              formula (1-29')                                                                        1-[1-(PNZ.N═)Et]-3-Pyrd                                                                      >CH.sub.2                                   1-52'                                                                            PNB                                                                              H Et     1-[1-(PNZ.N═)Et]-3-Pyrd                                                                      >CH.sub.2                                   1-53'                                                                            PNB                                                                              H 1-HO-1-MeEt                                                                          1-[1-(PNZ.N═)Et]-3-Pyrd                                                                      >CH.sub.2                                   1-54'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           1-[1-(PNZ.N═)Et]-3-Pyrd                                                                      >S                                          1-55'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           --CH.sub.2 CH.sub.2 NH.PNZ                                                                       >S                                          1-56'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           1-PNZ-5-Me.sub.2 NCO-3-Pyrd                                                                      >S                                          1-57'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           Tht                >S                                          1-58'                                                                            PNB                                                                              H 1-(G--O)Et                                                                           Et                 >CH(CH.sub.3)                               __________________________________________________________________________

                                      TABLE 5                                     __________________________________________________________________________    Cpd.                                                                          No.                                                                              k' R.sup.1'                                                                         R.sup.2'                                                                         R.sup.3'                                                                             R.sup.4'    X'                                             __________________________________________________________________________    2-1'                                                                             1  PNB                                                                              H  1-(G--O)Et                                                                           2-(Et.sub.2 NCO)Ph                                                                        >CH(CH.sub.3)                                  2-2'                                                                             2  PNB                                                                              H  1-(G--O)Et                                                                           2-(Et.sub.2 NCO)Ph                                                                        >CH(CH.sub.3)                                  2-3'                                                                             1  PNB                                                                              H  1-(G--O)Et                                                                           2-[1-Azp.CO)Ph                                                                            >CH(CH.sub.3)                                  2-4'                                                                             2  PNB                                                                              H  1-(G--O)Et                                                                           2-[1-Azp.CO)Ph                                                                            >CH(CH.sub.3)                                  2-5'                                                                             1  PNB                                                                              H  1-(G--O)Et                                                                           2-PyrMe     >CH(CH.sub.3)                                  2-6'                                                                             2  PNB                                                                              H  1-(G--O)Et                                                                           2-PyrMe     >CH(CH.sub.3)                                  2-7'                                                                             1  PNB                                                                              H  1-(G--O)Et                                                                           (3-Me-2-Pyr)Me                                                                            >CH(CH.sub.3)                                  2-8'                                                                             2  PNB                                                                              H  1-(G--O)Et                                                                           (3-Me-2-Pyr)Me                                                                            >CH(CH.sub.3)                                  2-9'                                                                             1  PNB                                                                              H  1-(G--O)Et                                                                           (1-Me-2-Imid)Me                                                                           >CH(CH.sub.3)                                  2-10'                                                                            2  PNB                                                                              H  1-(G--O)Et                                                                           (1-Me-2-Imid)Me                                                                           >CH(CH.sub.3)                                  2-11'                                                                            1  PNB                                                                              H  1-(G--O)Et                                                                           (3-Ithiz)Me >CH(CH.sub.3)                                  2-12'                                                                            2  PNB                                                                              H  1-(G--O)Et                                                                           (3-Ithiz)Me >CH(CH.sub.3)                                  2-13'                                                                            1  PNB                                                                              H  1-(G--O)Et                                                                           2-Pyr       >CH(CH.sub.3)                                  2-14'                                                                            2  PNB                                                                              H  1-(G--O)Et                                                                           2-Pyr       >CH(CH.sub.3)                                  2-15'                                                                            1  PNB                                                                              H  1-(G--O)Et                                                                           --CH.sub.2 CH.sub.2 NH.PNZ                                                                >CH(CH.sub.3)                                  2-16'                                                                            2  PNB                                                                              H  1-(G--O)Et                                                                           --CH.sub.2 CH.sub.2 NH.PNZ                                                                >CH(CH.sub.3)                                  2-17'                                                                            1  PNB                                                                              H  1-(G--O)Et                                                                           Ph          >CH(CH.sub.3)                                  2-18'                                                                            2  PNB                                                                              H  1-(G--O)Et                                                                           Ph          >CH(CH.sub.3)                                  2-19'                                                                            1  PNB                                                                              H  1-(G--O)Et                                                                           Et          >CH(CH.sub.3)                                  2-20'                                                                            2  PNB                                                                              H  1-(G--O)Et                                                                           Et          >CH(CH.sub.3)                                  2-21'                                                                            1  PNB                                                                              H  1-(G--O)Et                                                                           Bz          >CH(CH.sub.3)                                  2-22'                                                                            2  PNB                                                                              H  1-(G--O)Et                                                                           Bz          >CH(CH.sub.3)                                  2-23'                                                                            1  PNB                                                                              H  1-(G--O)Et                                                                           --CH.sub.2 CH.sub.2 NH.Ac                                                                 >CH.sub.2                                      2-24'                                                                            1  PNB                                                                              H  1-(G--O)Et                                                                           --CH.sub.2 CH.sub.2 NH.PNZ                                                                >CH.sub.2                                      2-25'                                                                            1  PNB                                                                              H  1-(G--O)Et                                                                           --CH.sub.2 CH.sub.2 OH                                                                    >CH.sub.2                                      2-26'                                                                            1  PNB                                                                              H  1-(G--O)Et                                                                           --CH═CH--NH.Ac                                                                        >CH.sub.2                                      2-27'                                                                            1  PNB                                                                              formula (1-30)                                                                          --CH.sub.2 CH.sub.2 NH.Ac                                                                 >CH.sub.2                                      2-28'                                                                            1  PNB                                                                              H  1-HO-1-MeEt                                                                          --CH.sub.2 CH.sub.2 NH.Ac                                                                 >CH.sub.2                                      2-29'                                                                            1  PNB                                                                              H  Et     --CH.sub.2 CH.sub.2 NH.Ac                                                                 >CH.sub.2                                      2-30'                                                                            1  PNB                                                                              H  1-(G--O)Et                                                                           Ph          >CH.sub.2                                      2-31'                                                                            1  PNB                                                                              H  1-(G--O)Et                                                                           Et          >CH.sub.2                                      2-32'                                                                            1  PNB                                                                              H  1-(G--O)Et                                                                           Bz          >CH.sub.2                                      2-33'                                                                            1  PNB                                                                              H  1-(G--O)Et                                                                           Et          >S                                             2-34'                                                                            1  PNB                                                                              H  1-(G--O)Et                                                                           --CH.sub.2 CH.sub.2 NH.PNZ                                                                >S                                             2-35'                                                                            1  All                                                                              H  1-(G--O)Et                                                                           2-(Et.sub.2 NCO)Ph                                                                        >CH(CH.sub.3)                                  2-36'                                                                            2  All                                                                              H  1-(G--O)Et                                                                           2-(Et.sub.2 NCO)Ph                                                                        >CH(CH.sub.3)                                  2-37'                                                                            1  All                                                                              H  1-(G--O)Et                                                                           (3-Me-2-Pyr)Me                                                                            >CH(CH.sub.3)                                  2-38'                                                                            2  All                                                                              H  1-(G--O)Et                                                                           (3-Me-2-Pyr)Me                                                                            >CH(CH.sub.3)                                  2-39'                                                                            1  All                                                                              H  1-(G--O)Et                                                                           (2-Pyr)Me   >CH(CH.sub.3)                                  2-40'                                                                            2  All                                                                              H  1-(G--O)Et                                                                           (2-Pyr)Me   >CH(CH.sub.3)                                  2-41'                                                                            1  All                                                                              H  1-(G--O)Et                                                                           2-Pyr       >CH(CH.sub.3)                                  2-42'                                                                            2  All                                                                              H  1-(G--O)Et                                                                           2-Pyr       >CH(CH.sub.3)                                  2-43'                                                                            1  All                                                                              H  1-(G--O)Et                                                                           Ph          >CH(CH.sub.3)                                  2-44'                                                                            2  All                                                                              H  1-(G--O)Et                                                                           Ph          >CH(CH.sub.3)                                  2-45'                                                                            1  All                                                                              H  1-(G--O)Et                                                                           Et          >CH(CH.sub.3)                                  2-46'                                                                            2  All                                                                              H  1-(G--O)Et                                                                           Et          >CH(CH.sub.3)                                  2-47'                                                                            1  All                                                                              H  1-(G--O)Et                                                                           Bz          >CH(CH.sub.3)                                  2-48'                                                                            2  All                                                                              H  1-(G--O)Et                                                                           Bz          >CH(CH.sub.3)                                  __________________________________________________________________________

                  TABLE 6                                                         ______________________________________                                        Cpd.                                                                          No.      R.sup.41'                                                                             R.sup.43'                                                                              R.sup.1'                                                                            R.sup.45'                                                                           R.sup.46'                                                                           i'                                ______________________________________                                        3-1'     TBS     H        PNB   Me    Me    0                                 3-2'     TBS     H        PNB   Me    Me    1                                 3-3'     TBS     H        PNB   Me    Me    2                                 3-4'     TBS     H        PNB   Et    Et    0                                 3-5'     TBS     H        PNB   Et    Et    1                                 3-6'     TBS     H        PNB   Et    Et    2                                 3-7'     TBS     H        PNB   Pr    Pr    0                                 3-8'     TBS     H        PNB   Pr    Pr    1                                 3-9'     TBS     H        PNB   Pr    Pr    2                                 3-10'    TBS     H        PNB   iPr   Pr    0                                 3-11'    TBS     H        PNB   iPr   Pr    1                                 3-12'    TBS     H        PNB   iPr   Pr    2                                 3-13'    TBS     H        PNB   Me    Et    0                                 3-14'    TBS     H        PNB   Me    Et    1                                 3-15'    TBS     H        PNB   Me    Et    2                                 3-16'    TBS     H        PNB   iBu   iBu   0                                 3-17'    TBS     H        PNB   iBu   iBu   1                                 3-18'    TBS     H        PNB   iBu   iBu   2                                 3-19'    TBS     H        PNB   Bu    Bu    0                                 3-20'    TBS     H        PNB   Bu    Bu    1                                 3-21'    TBS     H        PNB   Bu    Bu    2                                 3-22'    TBS     H        PNB   Et    Pr    0                                 3-23'    TBS     H        PNB   Et    Pr    1                                 3-24'    TBS     H        PNB   Et    Pr    2                                 3-25'    TBS     H        PNB   Me    Bu    0                                 3-26'    TBS     H        PNB   Me    Bu    1                                 3-27'    TBS     H        PNB   Me    Bu    2                                 3-28'    TMS     H        PNB   Me    Me    0                                 3-29'    TMS     H        PNB   Me    Me    1                                 3-30'    TMS     H        PNB   Me    Me    2                                 3-31'    TMS     H        PNB   Et    Et    0                                 3-32'    TMS     H        PNB   Et    Et    1                                 3-33'    TMS     H        PNB   Et    Et    2                                 3-34'    TMS     H        PNB   Pr    Pr    0                                 3-35'    TMS     H        PNB   Pr    Pr    1                                 3-36'    TMS     H        PNB   Pr    Pr    2                                 3-37'    TMS     H        PNB   iBu   iBu   0                                 3-38'    TMS     H        PNB   iBu   iBu   1                                 3-39'    TMS     H        PNB   iBu   iBu   2                                 3-40'    TMS     H        PNB   Bu    Bu    0                                 3-41'    TMS     H        PNB   Bu    Bu    1                                 3-42'    TMS     H        PNB   Bu    Bu    2                                 3-43'    TMS     H        PNB   iPr   Et    0                                 3-44'    TMS     H        PNB   iPr   Et    1                                 3-45'    TMS     H        PNB   iPr   Et    2                                 3-46'    H       H        PNB   Me    Me    0                                 3-47'    H       H        PNB   Me    Me    1                                 3-48'    H       H        PNB   Me    Me    2                                 3-49'    H       H        PNB   Et    Et    0                                 3-50'    H       H        PNB   Et    Et    1                                 3-51'    H       H        PNB   Et    Et    2                                 3-52'    H       H        PNB   Pr    Pr    0                                 3-53'    H       H        PNB   Pr    Pr    1                                 3-54'    H       H        PNB   Pr    Pr    2                                 3-55'    H       H        PNB   iBu   iBu   0                                 3-56'    H       H        PNB   iBu   iBu   1                                 3-57'    H       H        PNB   iBu   iBu   2                                 3-58'    H       H        PNB   Bu    Bu    0                                 3-59'    H       H        PNB   Bu    Bu    1                                 3-60'    H       H        PNB   Bu    Bu    2                                 3-61'    H       H        PNB   iPr   Et    0                                 3-62'    H       H        PNB   iPr   Et    1                                 3-63'    H       H        PNB   iPr   Et    2                                 3-64'    H       H        All   Me    Me    0                                 3-65'    H       H        All   Me    Me    1                                 3-66'    H       H        All   Me    Me    2                                 3-67'    H       H        All   Et    Et    0                                 3-68'    H       H        All   Et    Et    1                                 3-69'    H       H        All   Et    Et    2                                 3-70'    H       H        All   Pr    Pr    0                                 3-71'    H       H        All   Pr    Pr    1                                 3-72'    H       H        All   Pr    Pr    2                                 3-73'    H       H        All   iBu   iBu   0                                 3-74'    H       H        All   iBu   iBu   1                                 3-75'    H       H        All   iBu   iBu   2                                 3-76'    H       H        All   Bu    Bu    0                                 3-77'    H       H        All   Bu    Bu    1                                 3-78'    H       H        All   Bu    Bu    2                                 3-79'    TMS     H        All   Me    Me    0                                 3-80'    TMS     H        All   Me    Me    1                                 3-81'    TMS     H        All   Me    Me    2                                 3-82'    TMS     H        All   Et    Et    0                                 3-83'    TMS     H        All   Et    Et    1                                 3-84'    TMS     H        All   Et    Et    2                                 3-85'    TMS     H        All   Pr    Pr    0                                 3-86'    TMS     H        All   Pr    Pr    1                                 3-87'    TMS     H        All   Pr    Pr    2                                 3-88'    TMS     H        All   iBu   iBu   0                                 3-89'    TMS     H        All   iBu   iBu   1                                 3-90'    TMS     H        All   iBu   iBu   2                                 3-91'    TMS     H        All   Bu    Bu    0                                 3-92'    TMS     H        All   Bu    Bu    1                                 3-93'    TMS     H        All   Bu    Bu    2                                 3-94'    TBS     H        All   Me    Me    0                                 3-95'    TBS     H        All   Me    Me    1                                 3-96'    TBS     H        All   Me    Me    2                                 3-97'    TBS     H        All   Et    Et    0                                 3-98'    TBS     H        All   Et    Et    1                                 3-99'    TBS     H        All   Et    Et    2                                 3-100'   TBS     H        All   Pr    Pr    0                                 3-101'   TBS     H        All   Pr    Pr    1                                 3-102'   TBS     H        All   Pr    Pr    2                                 3-103'   TBS     H        All   iBu   iBu   0                                 3-104'   TBS     H        All   iBu   iBu   1                                 3-105'   TBS     H        All   iBu   iBu   2                                 3-106'   TBS     H        All   Bu    Bu    0                                 3-107'   TBS     H        All   Bu    Bu    1                                 3-108'   TBS     H        All   Bu    Bu    2                                 3-109'   TBS     H        All   Me    Et    0                                 3-110'   TBS     H        All   Me    Et    1                                 3-111'   TBS     H        All   Me    Et    2                                 3-112'   TMS     H        All   Me    Et    0                                 3-113'   TMS     H        All   Me    Et    1                                 3-114'   TMS     H        All   Me    Et    2                                 3-115'   H       H        All   Me    Et    0                                 3-116'   H       H        All   Me    Et    1                                 3-117'   H       H        All   Me    Et    2                                 3-118'   H       H        All   Et    Pr    0                                 3-119'   H       H        All   Et    Pr    1                                 3-120'   H       H        All   Et    Pr    2                                 3-121'   TMS     H        All   Et    Pr    0                                 3-122'   TMS     H        All   Et    Pr    1                                 3-123'   TMS     H        All   Et    Pr    2                                 3-124'   TBS     H        All   Et    Pr    0                                 3-125'   TBS     H        All   Et    Pr    1                                 3-126'   TBS     H        All   Et    Pr    2                                 3-127'   TMS     H        PNB   Me    Et    0                                 3-128'   TMS     H        PNB   Me    Et    1                                 3-129'   TMS     H        PNB   Me    Et    2                                 3-130'   H       H        PNB   Me    Et    0                                 3-131'   H       H        PNB   Me    Et    1                                 3-132'   H       H        PNB   Me    Et    2                                 3-133'   H       H        PNB   Et    Pr    0                                 3-134'   H       H        PNB   Et    Pr    1                                 3-135'   H       H        PNB   Et    Pr    2                                 3-136'   TMS     H        PNB   Et    Pr    0                                 3-137'   TMS     H        PNB   Et    Pr    1                                 3-138'   TMS     H        PNB   Et    Pr    2                                 3-139'   PNZ     H        PNB   Et    Et    0                                 3-140'   PNZ     H        PNB   Et    Et    1                                 3-141'   PNZ     H        PNB   Et    Et    2                                 3-142'   PNZ     H        PNB   Me    Me    0                                 3-143'   PNZ     H        PNB   Me    Me    1                                 3-144'   PNZ     H        PNB   Me    Me    2                                 3-145'   PNZ     H        PNB   iBu   iBu   0                                 3-146'   PNZ     H        PNB   iBu   iBu   1                                 3-147'   PNZ     H        PNB   iBu   iBu   2                                 3-148'   PNZ     H        PNB   Bu    Bu    0                                 3-149'   PNZ     H        PNB   Bu    Bu    1                                 3-150'   PNZ     H        PNB   Bu    Bu    2                                 3-151'   PNZ     H        PNB   Ph    Pr    0                                 3-152'   PNZ     H        PNB   Ph    Pr    1                                 3-153'   PNZ     H        PNB   Ph    Pr    2                                 3-154'   PNZ     H        All   Et    Et    0                                 3-155'   PNZ     H        All   Et    Et    1                                 3-156'   PNZ     H        All   Et    Et    2                                 3-157'   TBS     H        PNB   Me    Ph    0                                 3-158'   TBS     H        PNB   Me    Ph    1                                 3-159'   TBS     H        PNB   Me    Ph    2                                 3-160'   TMS     H        PNB   Me    Ph    0                                 3-161'   TMS     H        PNB   Me    Ph    1                                 3-162'   TMS     H        PNB   Me    Ph    2                                 3-163'   H       H        PNB   Me    Ph    0                                 3-164'   H       H        PNB   Me    Ph    1                                 3-165'   H       H        PNB   Me    Ph    2                                 3-166'   TBS     H        PNB   Et    Ph    0                                 3-167'   TBS     H        PNB   Et    Ph    1                                 3-168'   TBS     H        PNB   Et    Ph    2                                 3-169'   TMS     H        PNB   Et    Ph    0                                 3-170'   TMS     H        PNB   Et    Ph    1                                 3-171'   TMS     H        PNB   Et    Ph    2                                 3-172'   H       H        PNB   Et    Ph    0                                 3-173'   H       H        PNB   Et    Ph    1                                 3-174'   H       H        PNB   Et    Ph    2                                 3-175'   TBS     6-Me     PNB   Et    Et    1                                 3-176'   TBS     5-Me     PNB   Et    Et    1                                 3-177'   TBS     4-Me     PNB   Et    Et    1                                 3-178'   TBS     5-NO.sub.2                                                                             PNB   Et    Et    1                                 3-179'   TBS     5-Cl     PNB   Et    Et    1                                 3-180'   TBS     4-OMe    PNB   Et    Et    1                                 3-181'   TBS     6-Cl     PNB   Et    Et    1                                 3-182'   TBS     3-Me     PNB   Et    Et    1                                 ______________________________________                                    

                  TABLE 7                                                         ______________________________________                                        Cpd.                                                                          No.   R.sup.41'                                                                             R.sup.43'                                                                             R.sup.1'                                                                            A'           i'                                   ______________________________________                                        4-1'  TBS     H       PNB   --(CH.sub.2).sub.2 --                                                                      0                                    4-2'  TBS     H       PNB   --(CH.sub.2).sub.3 --                                                                      0                                    4-3'  TBS     H       PNB   --(CH.sub.2).sub.4 --                                                                      0                                    4-4'  TBS     H       PNB   --(CH.sub.2).sub.5 --                                                                      0                                    4-5'  TBS     H       PNB   --(CH.sub.2).sub.6 --                                                                      0                                    4-6'  TBS     H       PNB   --(CH.sub.2).sub.7 --                                                                      0                                    4-7'  TBS     H       PNB   --(CH.sub.2).sub.2 O(CH.sub.2).sub.2 --                                                    0                                    4-8'  TBS     H       PNB   --(CH.sub.2).sub.2 --                                                                      1                                    4-9'  TBS     H       PNB   --(CH.sub.2).sub.3 --                                                                      1                                    4-10' TBS     H       PNB   --(CH.sub.2).sub.4 --                                                                      1                                    4-11' TBS     H       PNB   --(CH.sub.2).sub.5 --                                                                      1                                    4-12' TBS     H       PNB   --(CH.sub.2).sub.6 --                                                                      1                                    4-13' TBS     H       PNB   --(CH.sub.2).sub.7 --                                                                      1                                    4-14' TBS     H       PNB   --(CH.sub.2).sub.2 O(CH.sub.2).sub.2 --                                                    1                                    4-15' TBS     H       PNB   --(CH.sub.2).sub.2 --                                                                      2                                    4-16' TBS     H       PNB   --(CH.sub.2).sub.3 --                                                                      2                                    4-17' TBS     H       PNB   --(CH.sub.2).sub.4 --                                                                      2                                    4-18' TBS     H       PNB   --(CH.sub.2).sub.5 --                                                                      2                                    4-19' TBS     H       PNB   --(CH.sub.2).sub.6 --                                                                      2                                    4-20' TBS     H       PNB   --(CH.sub.2).sub.7 --                                                                      2                                    4-21' TBS     H       PNB   --(CH.sub.2).sub.2 O(CH.sub.2).sub.2 --                                                    2                                    4-22' TMS     H       PNB   --(CH.sub.2).sub.2 --                                                                      0                                    4-23' TMS     H       PNB   --(CH.sub.2).sub.3 --                                                                      0                                    4-24' TMS     H       PNB   --(CH.sub.2).sub.4 --                                                                      0                                    4-25' TMS     H       PNB   --(CH.sub.2).sub.5 --                                                                      0                                    4-26' TMS     H       PNB   --(CH.sub.2).sub.6 --                                                                      0                                    4-27' TMS     H       PNB   --(CH.sub.2).sub.7 --                                                                      0                                    4-28' TMS     H       PNB   --(CH.sub.2).sub.2 O(CH.sub.2).sub.2 --                                                    0                                    4-29' TMS     H       PNB   --(CH.sub.2).sub.2 --                                                                      1                                    4-30' TMS     H       PNB   --(CH.sub.2).sub.3 --                                                                      1                                    4-31' TMS     H       PNB   --(CH.sub.2).sub.4 --                                                                      1                                    4-32' TMS     H       PNB   --(CH.sub.2).sub.5 --                                                                      1                                    4-33' TMS     H       PNB   --(CH.sub.2).sub.6 --                                                                      1                                    4-34' TMS     H       PNB   --(CH.sub.2).sub.7 --                                                                      1                                    4-35' TMS     H       PNB   --(CH.sub.2).sub.2 O(CH.sub.2).sub.2 --                                                    1                                    4-36' TMS     H       PNB   --(CH.sub.2).sub.2 --                                                                      2                                    4-37' TMS     H       PNB   --(CH.sub.2).sub.3 --                                                                      2                                    4-38' TMS     H       PNB   --(CH.sub.2).sub.4 --                                                                      2                                    4-39' TMS     H       PNB   --(CH.sub.2).sub.5 --                                                                      2                                    4-40' TMS     H       PNB   --(CH.sub.2).sub.6 --                                                                      2                                    4-41' TMS     H       PNB   --(CH.sub.2).sub.7 --                                                                      2                                    4-42' TMS     H       PNB   --(CH.sub.2).sub.2 O(CH.sub.2).sub.2 --                                                    2                                    4-43' H       H       PNB   --(CH.sub.2).sub.2 --                                                                      0                                    4-44' H       H       PNB   --(CH.sub.2).sub.3 --                                                                      0                                    4-45' H       H       PNB   --(CH.sub.2).sub.4 --                                                                      0                                    4-46' H       H       PNB   --(CH.sub.2).sub.5 --                                                                      0                                    4-47' H       H       PNB   --(CH.sub.2).sub.6 --                                                                      0                                    4-48' H       H       PNB   --(CH.sub.2).sub.7 --                                                                      0                                    4-49' H       H       PNB   --(CH.sub.2).sub.2 O(CH.sub.2).sub.2 --                                                    0                                    4-50' H       H       PNB   --(CH.sub.2).sub.2 --                                                                      1                                    4-51' H       H       PNB   --(CH.sub.2).sub.3 --                                                                      1                                    4-52' H       H       PNB   --(CH.sub.2).sub.4 --                                                                      1                                    4-53' H       H       PNB   --(CH.sub.2).sub.5 --                                                                      1                                    4-54' H       H       PNB   --(CH.sub.2).sub.6 --                                                                      1                                    4-55' H       H       PNB   --(CH.sub.2).sub.7 --                                                                      1                                    4-56' H       H       PNB   --(CH.sub.2).sub.2 O(CH.sub.2).sub.2 --                                                    1                                    4-57' H       H       PNB   --(CH.sub.2).sub.2 --                                                                      2                                    4-58' H       H       PNB   --(CH.sub.2).sub.3 --                                                                      2                                    4-59' H       H       PNB   --(CH.sub.2).sub.4 --                                                                      2                                    4-60' H       H       PNB   --(CH.sub.2).sub.5 --                                                                      2                                    4-61' H       H       PNB   --(CH.sub.2).sub.6 --                                                                      2                                    4-62' H       H       PNB   --(CH.sub.2).sub.7 --                                                                      2                                    4-63' H       H       PNB   --(CH.sub.2).sub.2 O(CH.sub.2).sub.2 --                                                    2                                    4-64' H       H       All   --(CH.sub.2).sub.4 --                                                                      0                                    4-65' H       H       All   --(CH.sub.2).sub.5 --                                                                      0                                    4-66' H       H       All   --(CH.sub.2).sub.6 --                                                                      0                                    4-67' H       H       All   --(CH.sub.2).sub.6 --                                                                      1                                    4-68' H       H       All   --(CH.sub.2).sub.5 --                                                                      1                                    4-69' H       H       All   --(CH.sub.2).sub.4 --                                                                      1                                    4-70' H       H       All   --(CH.sub.2).sub.4 --                                                                      2                                    4-71' H       H       All   --(CH.sub.2).sub.5 --                                                                      2                                    4-72' H       H       All   --(CH.sub.2).sub.6 --                                                                      2                                    4-73' TMS     H       All   --(CH.sub.2).sub.6 --                                                                      0                                    4-74' TMS     H       All   --(CH.sub.2).sub.5 --                                                                      0                                    4-75' TMS     H       All   --(CH.sub.2).sub.4 --                                                                      0                                    4-76' TMS     H       All   --(CH.sub.2).sub.4 --                                                                      1                                    4-77' TMS     H       All   --(CH.sub.2).sub.5 --                                                                      1                                    4-78' TMS     H       All   --(CH.sub.2).sub.6 --                                                                      1                                    4-79' TMS     H       All   --(CH.sub.2).sub.6 --                                                                      2                                    4-80' TMS     H       All   --(CH.sub.2).sub.5 --                                                                      2                                    4-81' TMS     H       All   --(CH.sub.2).sub.4 --                                                                      2                                    4-82' TBS     H       All   --(CH.sub.2).sub.4 --                                                                      0                                    4-83' TBS     H       All   --(CH.sub.2).sub.5 --                                                                      0                                    4-84' TBS     H       All   --(CH.sub.2).sub.6 --                                                                      0                                    4-85' TBS     H       All   --(CH.sub.2).sub.6 --                                                                      1                                    4-86' TBS     H       All   --(CH.sub.2).sub.5 --                                                                      1                                    4-87' TBS     H       All   --(CH.sub.2).sub.4 --                                                                      1                                    4-88' TBS     H       All   --(CH.sub.2).sub.4 --                                                                      2                                    4-89' TBS     H       All   --(CH.sub.2).sub.5 --                                                                      2                                    4-90' TBS     H       All   --(CH.sub.2).sub.6 --                                                                      2                                    4-91' PNZ     H       PNB   --(CH.sub.2).sub.6 --                                                                      0                                    4-92' PNZ     H       PNB   --(CH.sub.2).sub.5 --                                                                      0                                    4-93' PNZ     H       PNB   --(CH.sub.2).sub.4 --                                                                      0                                    4-94' PNZ     H       PNB   --(CH.sub.2).sub.4 --                                                                      1                                    4-95' PNZ     H       PNB   --(CH.sub.2).sub.5 --                                                                      1                                    4-96' PNZ     H       PNB   --(CH.sub.2).sub.6 --                                                                      1                                    4-97' PNZ     H       PNB   --(CH.sub.2).sub.6 --                                                                      2                                    4-98' PNZ     H       PNB   --(CH.sub.2).sub.5 --                                                                      2                                    4-99' TBS     4-Me    PNB   --(CH.sub.2).sub.6 --                                                                      1                                    4-100'                                                                              TBS     5-Cl    PNB   --(CH.sub.2).sub.6 --                                                                      1                                    4-101'                                                                              TBS     5-NO.sub.2                                                                            PNB   --(CH.sub.2).sub.6 --                                                                      1                                    4-102'                                                                              TBS     6-Cl    PNB   --(CH.sub.2).sub.6 --                                                                      1                                    4-103'                                                                              TBS     4-Me    PNB   --(CH.sub.2).sub.6 --                                                                      0                                    4-104'                                                                              TBS     5-Cl    PNB   --(CH.sub.2).sub.6 --                                                                      0                                    4-105'                                                                              TBS     5-NO.sub.2                                                                            PNB   --(CH.sub.2).sub.6 --                                                                      0                                    4-106'                                                                              TBS     6-Cl    PNB   --(CH.sub.2).sub.6 --                                                                      0                                    4-107'                                                                              TBS     4-Me    PNB   --(CH.sub.2).sub.6 --                                                                      2                                    4-108'                                                                              TBS     5-Cl    PNB   --(CH.sub.2).sub.6 --                                                                      2                                    4-109'                                                                              TBS     5-NO.sub.2                                                                            PNB   --(CH.sub.2).sub.6 --                                                                      2                                    4-110'                                                                              TBS     6-Cl    PNB   --(CH.sub.2).sub.6 --                                                                      2                                    4-111'                                                                              TBS     4-Me    PNB   --(CH.sub.2).sub.4 --                                                                      1                                    4-112'                                                                              TBS     5-Cl    PNB   --(CH.sub.2).sub.4 --                                                                      1                                    4-113'                                                                              TBS     5-NO.sub.2                                                                            PNB   --(CH.sub.2).sub.4 --                                                                      1                                    ______________________________________                                    

Of the compounds listed in above preferred compounds are Compounds No.3-1', 3-2', 3-3', 3-4', 3-5', 3-6', 3-7', 3-8', 3-9', 3-28', 3-29',3-30', 3-31', 3-32', 3-33', 3-34', 3-35', 3-36', 3-47', 3-48', 3-40',3-50', 3-51', 3-52', 3-53', 3-54', 3-64', 3-65', 3-66', 3-67', 3-68',3-69', 3-79', 3-80', 3-81', 3-82', 3-83', 3-84', 4-3', 4-4', 4-5', 4-7',4-10', 4-11', 4-12', 4-14', 4-17', 4-18', 4-19', 4-21', 4-24', 4-26',4-4-28', 4-31', 4-33', 4-35', 4-38', 4-40', 4-42', 4-45', 4-47', 4-49',4-52', 4-54', 4-56', 4-59', 4-61' and 4-63'. More preferred compoundsare Compounds No. 3-4', 3-5', 3-6', 3-31', 3-32', 3-33', 3-49', 3-50',3-51', 4-5', 4-12', 4-19', 4-26', 4-33', 4-40', 4-47', 4-54' and 4-61'.The most preferred compounds are Compounds No.

3-31'. 4-Nitrobenzyl2-(2-diethylcarbamoylphenylthio)-1-methyl-6-(1-trimethylsilyloxyethyl)-1-carbapen-2-em-3-carboxylate;

3-32'. 4-Nitrobenzyl2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-(1-trimethylsilyloxyethyl)-2-carbapen-2-em-3-carboxylate;

3-33'. 4-Nitrobenzyl2-(2-diethylcarbamoylphenylsulfonyl)-1-methyl-6-(1-trimethylsilyloxyethyl)-1-carbapen-2-em-3-carboxylate;

3-40'. 4-Nitrobenzyl-2-(2-diethylcarbamoylphenylthio)-2-methyl-6-(1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate;

3-50'. 4-Nitrobenzyl2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-(1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate;

3-51'. 4-Nitrobenzyl2-(2-diethylcarbamoylphenylsulfonyl)-1-methyl-6-(1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate;

4-26'. 4-Nitrobenzyl2-[2-(1-perhydroazepinylcarbonyl)-phenylthio]-1-methyl-6-(1-trimethylsilyloxyethyl)-1-carbapen-2-em-3-carboxylate;

4-33'. 4-Nitrobenzyl2-[2-(1-perhydroazepinylcarbonyl)-phenylsulfinyl]-1-methyl-6-(1-trimethylsilyloxyethyl)-1-carbapen-2-em-3-carboxylate;

4-40'. 4-Nitrobenzyl2-[2-(1-perhydroazepinylcarbonyl)-phenylsulfonyl]-1-methyl-6-(1-trimethylsilyloxyethyl)-1-carbapen-2-em-3-carboxylate;

4-47'. 4-Nitrobenzyl2-[2-(1-perhydroazepinylcarbonyl)-phenylthio]-1-methyl-6-(1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate;and

4-54'. 4-Nitrobenzyl2-[2-(1-perhydroazepinylcarbonyl)-phenylsulfinyl]-1-methyl-6-(1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate;and

4-61'. 4-Nitrobenzyl2-[2-(1-perhydroazepinylcarbonyl)-phenylsulfonyl]-1-methyl-6-(1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate.

In accordance with the present invention, compounds of formula (II'),which include the novel compounds of formula (IV'), may be converte tothe desired compounds of formula (I') by reaction with a compound offormula (III'), A'SH (in which A' is as defined above), in the presenceof a metal salt. The metal salt is a salt of a metal from Group II orIII of the Periodic Table.

In the case of salts of a metal belonging to Group II, the metal may befrom sub-Group A or B. The metals of sub-Group A include beryllium,magnesium, calcium, strontium, barium and radium. The metals ofsub-Group B of Group II include zinc, cadmium and mercury, but these arenot preferred for use in the process of the present invention.Accordingly, the metals of sub-Group A are preferred, magnesium orcalcium salts being especially preferred and the salts of magnesiumbeing most preferred. Of these, we particularly prefer:

a metal halide, such as magnesium chloride, magnesium bromide, magnesiumiodide or calcium bromide;

a complex of the metal with an ether such as magnesium bromide--diethylether complex;

a mixture of the metal halide or of the ether complex with an organicbase such as triethylamine, diisopropylethylamine, 1-ethylpiperidine,1,5-diazabicyclo[5,4,0]-5-undecene, 1,4-diazabicyclo[2,2,2]octane or1,5-diazabicyclo[4,3,0]-5-nonene [which mixture can, for example, beprepared by suspending a halide of a metal belonging to Group II or itsether complex in a solvent, and then adding an organic base (The molarratio of the metal salt to the organic base is preferably from 10:1 to1:1];

an amide of a metal belonging to Group II and having the formula (V'):

    R.sup.33' R.sup.34' N.M--X'                                (V)

in which:

each of R^(33') and R^(34') independently represents a straight orbranched chain alkyl group, preferably having from 1 to 6, morepreferably from 1 to 4, carbon atoms, such as the methyl, ethyl andisopropyl groups; a cycloalkyl group, preferably having from 3 to 7,more preferably 5 or 6, carbon atoms, such as the cyclohexyl andcyclopentyl groups; a phenyl group; or a trialkylsilyl group in whicheach alkyl part preferably has from 1 to 6, more preferably from 1 to 4,carbon atoms, such as the trimethylsilyl group; or R^(33') and R^(34')together represent a group of formula --(CH₂)_(d') --, in which d'represents 4 or 5, or a group of formula --(CH₂)₂ O(CH₂)₂ --;

M' represents a metal belonging to Group II; and

X' represents a halogen atom, such as a chlorine, bromine or iodineatom;

an alcoholate of a metal belonging to Group II and having the formula(VI'):

    R.sup.35' --O--M'--X'                                      (VI')

in which:

R^(35') represents a straight or branched chain alkyl group, preferablyhaving from 1 to 6, more preferably from 1 to 4, carbon atoms, such asthe methyl, ethyl, isopropyl and t-butyl groups; a cycloalkyl group,preferably having from 3 to 7, more preferably 5 or 6, carbon atoms,such as the cyclohexyl and cyclopentyl groups; or a phenyl group;

M' represents a metal belonging to Group II; and

X' represents a halogen atom, such as a chlorine, bromine or iodineatom;

this compound of formula (VI') may be prepared by dissolving a compoundof formula R^(35') OH corresponding to the solvent employed for thereaction, and then allowing it to react with a Grignard reagent, such asmethyl magnesium bromide or phenyl magnesium bromide] or;

a mixture prepared by adding an alkali metal amide [such as lithiumbis(trimethylsilyl)amide, lithium diisopropylamide or sodiumbis(trimethylsilyl)amide] or an alkali metal alcoholate (such aspotassium t-butoxide or lithium ethoxide) to a halide of a metal or anether complex of a halide of a metal belonging to Group II suspended inthe solvent to be employed for the reaction.

In the case of Group III of the Periodic Table, sub-Group A includesscandium, yttrium and the lanthanides, but it is not certain that theywill be effective in the process of the present invention. Group IIIBincludes boron, aluminum, gallium, indium and thallium, and a salt of ametal from this sub-Group is preferred, a salt of aluminum or boronbeing more preferred and aluminum being most preferred. Examples ofsalts of metals belonging to Group III employable for the reactioninclude compounds of formula (VII'):

    R.sup.33' R.sup.34' N--Al(R.sup.36').sub.3                 (VII')

in which:

R^(33') and R^(34') are as defined above, and R^(36') represents analkyl group, preferably having from 1 to 6, more preferably from 1 to 4,carbon atoms, such as the methyl or ethyl groups.

From all of the metals of Groups II and III, we prefer magnesium,aluminum, beryllium, calcium and boron.

Of all of these salts, the most preferred are: magnesiumbromide--diethyl ether complex; a mixture of magnesium bromide--diethylether complex with diisopropylethylamine, 1-ethylpiperidine or1,4-diazabicyclo[5,4,0]-5-undecene; bromomagnesiumcyclohexylisopropylamide, bromomagnesium diisopropylamide,bromomagnesium diethylamide or bromomagnesium hexamethyldisilazide;bromomagnesium t-butoxide; a mixture of lithium diisopropylamide orlithium bistrimethylsilylamide with magnesium bromide--diethyl ethercomplex; or diethylaluminium diisopropylamide.

There is no particular restriction on the relative amounts of thereagents and of the metal salt employed. However, in general, we preferto employ the compound of formula (II') and the mercaptan of formula(III') in a molar ration of from 1:1 to 1:3. The salt of a metal ofGroup II or III is preferably present in an amount of from 1 to 20 molesper mole of the compound of formula (II').

The reaction is normally and preferably carried out in the presence of asolvent, the nature of which is not critical, provided that it has noadverse effect upon the reaction and that it can dissolve the reagents,at least to some extent. Examples of suitable solvents include:hydrocarbons, especially alicyclic and aromatic hydrocarbons, such ascyclohexane, benzene, toluene or xylene; halogenated hydrocarbons,especially halogenated aliphatic hydrocarbons, such as methylenechloride, 1,2-dichloroethane or carbon tetrachloride; ethers, such asdiethyl ether, 1,2-dimethoxyethane, tetrahydrofuran or dioxane; amides,such as dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone orhexamethylphosphoric triamide; and sulfoxides, such as dimethylsulfoxide. Of these, we prefer the hydrocarbons, the halogenatedhydrocarbons, the ethers or the amides, the ethers being particularlypreferred.

The reaction will take place over a wide range of temperatures, and theprecise reaction temperature chosen is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature in the range of from -70° C. to 60° C., more preferably from0° C. to 30° C. The time required for the reaction may likewise varywidely, depending on many factors, notably the reaction temperature andthe nature of the reagents. However, in most cases, a period of from 10minutes to 48 hours will normally suffice if a sulfinyl derivative isused, and from 10 minutes to several days will normally suffice if asulfonyl derivative is used.

A sulfinyl derivative of formula (IX') or a sulfonyl derivative offormula (X'), which may be used as the starting material for thisreaction, can be synthesized by oxidation of a compound of formula (XI')according to a known method using a suitable oxidizing agent, forexample a peroxide, such as m-chloroperbenzoic acid, peracetic acid ort-butyl peroxide, as shown in the following Reaction Scheme 2: ##STR29##

In the above formulae, R^(1'), R^(2'), R^(3') and R⁴ ' are as definedabove.

When t-butyl peroxide is used, we prefer to employ vanadylacetylacetonate [VO(acac)₂ ] as a catalyst. In addition, in order toremove any acidic substances originating from the peroxides which areformed in this reaction, the oxidation reaction is preferably conductedin the presence of a base, for example an alkali metal carbonate or anaqueous solution thereof.

A sulfonyl derivative of formula (X') can be synthesized either byfurther oxidation of the sulfinyl derivative of formula (IX') accordingto the method mentioned above or by direct oxidation of the compound offormula (XI').

These oxidation reactions are described in more detail in relation toStep 3d of Reaction Scheme 3.

The compound of formula (XI') employed as the starting material can besynthesized from a natural substance when X' represents CH₂ (forexample, as described by S. M. Schmitt et al.: J. Org. Chem. 1980, 45,1142); or according to the reported method when X represents CH₂ orCH(CH₃) [for example, as described by S. Oida et al.: TetrahedronLetters 25, 2793 (1984); B. G. Christensen et al.: Heterocycles 21, 29(1984)].

When X' represents a sulfur atom in the compound of formula (XI'), thecompound can be synthesized, for example, according to the followingreported methods [S. Oida et al.: Chem. Pharm. Bull. 29, 3158 (1981); A.Yoshida et al.: Chem. Pharm. Bull. 31, 768 (1983)].

Preferred examples of compounds of formula A'SH (III') employed in thepresent invention are those compounds of formula (IIIa') to (IIIf'):##STR30##

The compound of formula (I') which is obtainable by the method of thepresent invention can be converted into a corresponding carbapenem orpenem derivative having excellent antibacterial activity, by removal ofa carboxy-protecting group shown by R^(1'), and in some cases by removalof hydroxy-protecting groups shown by R^(2') and R^(3') at position 6and any protecting group in A' by conventional means.

The compounds of formula (IV') of the present invention may be prepared,for example, as illustrated by the following Reaction Scheme 3:##STR31##

In the above formulae, R^(1'), R⁴¹ ', R^(42'), R^(43'), R^(45'), R^(46')and Y' are as defined above.

R^(48') represents an alkyl group having from 1 to 6 carbon atoms or analkoxy group having from 1 to 6 carbon atoms. Where R^(48') representsan alkyl group having from 1 to 6 carbon atoms, it may be, for example,any of those groups exemplified above in relation to R^(2'),particularly a methyl, ethyl, propyl, isopropyl, butyl or isobutylgroup.

Where R^(48') represents an alkoxy group having from 1 to 6 carbonatoms, it may be, for example, any of those groups exemplified above inrelation to R^(7'), particularly a methoxy, ethoxy, propoxy, isopropoxy,butoxy, isobutoxy or t-butoxy group.

R^(49') represents an alkoxy group having from 1 to 6 carbon atoms or anaryloxy group (in which the aryl part may be as generally defined andexemplified above). Where R^(49') represents an alkoxy group, it may bethe same alkoxy group as defined and exemplified for R^(48').

Where R^(49') represents an aryloxy group, it may be, for example, aphenoxy, 4-methylphenoxy or 4-methoxyphenoxy group.

i" is 1 or 2.

A compound of formula (XII'), wherein R^(41') represents at-butyldimethylsilyl group, R^(42') represents a methyl group, the groupof formula --C(═Y')NR^(45') R^(46') represents a group of formula--CONEt₂ at the 2-position and R^(43') represents a hydrogen atom,(disclosed in Japanese Patent Application No. Hei 4-174099) which may bebe used as a starting material in Reaction Scheme 3, can be prepared byreactingZ(O)-1-t-butyldimethylsilyloxy-1-(diethylcarbamoylphenylthio)-1-propenewith (3R,4R)-3-(1(R)-[t-butyldimethylsilyloxy)ethyl]-4-acetoxyazetidinone, and isobtained in a 77% yield. It may be purified by recrystallization onlywithout carrying out column chromatography. Accordingly this compound isa valuable intermediate in the industrial preparation of13-methylcarbapenem derivatives.

Reaction Scheme 3 involves the preparation of a compound of formula(IVa') by reacting a compound of formula (XII') with an acid chloride offormula (XIII') to produce a N-oxalyl derivative of formula (XIV') andthen treating the product with a phosphorous acid triester orphosphonous acid diester. The reaction can be accomplished by the wellknown method described in Tetrahedron Letters, 25, 2793 (1984) orJapanese Patent Application No. Hei 4-180779.

Step 3a:

A compound of formula (XIV') can be prepared by reacting a compound offormula (XII') with an acid chloride or formula (XIII') in the presenceof a base. We prefer to employ from 2 to 5 equivalents of the acidchloride of formula (XIII') per equivalent of the compound of formula(XII').

There is no particular limitation upon the nature of the base used,provided that it has no adverse effect upon the reaction. Examples ofsuitable bases include: cyclic or linear tertiary amines, such asdiisopropylethylamine, diisopropylmethylamine, triethylamine,1-ethylpiperidine, 1-methylmorpholine, 1-ethylpyrrolidine,1,4-diazabicyclo[2,2,2]octane, 1,5-diazabicyclo[5,4,0]undec-5-ene or1,5-diazabicyclo[4,3,0]-non-5-ene.

The reaction is normally and preferably effected in the presence of asolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor on the reagents involved and that it can dissolve the reagents, atleast to some extent. Examples of suitable solvents include: halogenatedhydrocarbons, especially halogenated aliphatic hydrocarbons, such asmethylene chloride, chloroform or dichloroethane; ethers, such asdiethyl ether or tetrahydrofuran; hydrocarbons, especially aromatichydrocarbons, such as benzene or toluene; and nitriles such asacetonitrile or propionitrile.

The reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature of from -78° C. to 50° C., more preferably from -30° C. to30° C. The time required for the reaction may also vary widely,depending on many factors, notably the reaction temperature and thenature of the reagents and solvent employed. However, provided that thereaction is effected under the preferred conditions outlined above, aperiod of from 5 minutes to 3 hours will usually suffice.

After completion of the reaction, the desired compound can be recoveredfrom the reaction mixture by conventional means after, if necessary,decomposing any excess of the acid halide with an alcohol. An example ofone such technique comprises: adding water to the reaction mixture;extracting the desired compound of formula (XIV') with a water-insolubleorganic solvent such as the said reaction solvent or ethyl acetate; anddistilling off the solvent from the extract. The compound thus obtainedcan, if necessary, by purified by conventional means, such as columnchromatography.

Step 3b:

A phosphorane of formula (XVI') can be prepared by reacting a compoundof formula (XIV') with a tri-valent phosphorous compound of formula(XV') in the presence or absence of a solvent. There is no particularrestriction on the relative proportions of the reagents. However, wegenerally prefer to employ from 2 to 6 equivalents of the tri-valentphosphorous compound of formula (XV') per equivalent of the compound offormula (XIV').

The reaction may be effected in the absence or the presence of asolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor on the reagents involved and that it can dissolve the reagents, atleast to some extent. Examples of suitable solvents include:hydrocarbons, especially aromatic hydrocarbons, such as benzene, tolueneor xylane; halogenated hydrocarbons, especially halogenated aliphatichydrocarbons, such as chloroform, methylene chloride or1,2-dichloroethane; ethers, such as tetrahydrofuran or dioxane;nitriles, such as acetonitrile; esters, such as ethyl acetate; andamides, such as dimethylformamide.

The reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature of from -10° C. to 100° C., more preferably from 0° C. to100° C. The time required for the reaction may also vary widely,depending on many factors, notably the reaction temperature and thenature of the reagents and solvent employed. However, provided that thereaction is effected under the preferred conditions outlined above, aperiod of from 10 minutes to 30 hours will usually suffice.

After completion of the reaction, the desired phosphorane of formula(XVI') can be recovered from the reaction mixture by distilling off anyexcess of a phosphorous compound of formula (XV') and its oxygen-aductunder reduced pressure, or by precipitating the product by adding anon-polar solvent, such as hexane, to the reaction mixture.

The crude product of formula (XVI') thus obtained can be used in thesubsequent step without any purification. However, the product can, ifnecessary, be purified by conventional means, such as columnchromatography.

Step 3c:

The compound of formula (IVa') can be prepared by heating thephosphorane of formula (XVI').

The reaction is normally and preferably effected in the presence of asolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor on the reagents involved and that it can dissolve the reagents, atleast to some extent. Examples of suitable solvents include: substitutedaromatic hydrocarbons, such as toluene, xylene, mesitylene orchlorobenzene.

The reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature of from 100° C. to 200° C., more preferably from 120° C. to170° C. The time required for the reaction may also vary widely,depending on many factors, notably the reaction temperature and thenature of the reagents and solvent employed. However, provided that thereaction is effected under the preferred conditions outlined above, aperiod of from 1 to 30 hours will usually suffice.

After completion of the reaction, the product of formula (IVa') can berecovered from the reaction mixture by distilling off the solvent andrecrystallizing or chromatographing the residue.

Step 3d:

This optional step for the preparation of a compound of formula (Ib')involves oxidizing a compound of formula (IVa').

An S-oxide compound of formula (IVb') can be prepared by reacting thecompound of formula (IVa') with an oxidizing agent. Examples ofoxidizing agents which may be used include: peroxides, such as3-chloroperoxybenzoic acid, peracetic acid, hydrogen peroxide or t-butylhydroperoxide, perferably 3-chloroperoxybenzoic acid or t-butylperoxide. When t-butyl peroxide is used as an oxidizing agent in thereaction, the reaction is preferably carried out in the presence of acatalyst, such as vanadyl acetylacetonate or molybdenyl acetylacetonate,preferably vanadyl acetylacetonate. In order to remove any acidicsubstance arising from such oxidizing agents in the course of thereaction, the oxidation reaction can be carried out in the presence of abase, such as an alkali metal carbonate or an aqueous solution thereof.

The reaction is normally and preferably effected in the presence of asolvent. There is no particular restriction on the nature of the solventto be employed, provided that it has no adverse effect on the reactionor on the reagents involved and that it can dissolve the reagents, atleast to some extent. Examples of suitable solvents include: alcohols,such as methanol or ethanol; and halogenated hydrocarbons, especiallyhalogenated aliphatic hydrocarbons, such as methylene chloride,chloroform or 1,2-dichloroethane, of which the halogenated hydrocarbonsare preferred.

The reaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. Ingeneral, we find it convenient to carry out the reaction at atemperature of from -10° C. to 50° C., more preferably from 0° C. to 25°C. The time required for the reaction may also vary widely, depending onmany factors, notably the reaction temperature and the nature of thereagents and solvent employed. However, provided that the reaction iseffected under the preferred conditions outlined above, a period of from30 minutes to 6 hours will usually suffice.

After completion of the reaction, the compound of formula (IVb') can berecovered from the reaction mixture by the following means. Any excessof the oxidizing agent is decomposed by adding a 10% aqueous solution ofsodium sulfite and then the reaction mixture is diluted with a solventsuch as methylene chloride, washed with water and dried, after which thesolvent is distilled off.

The resulting residue may be purified by conventional means, such asrecrystallization or chromatography to give the compound of formula(IVb').

It is possible to prepare either the sulfinyl compound of formula (IVb')(i" is 1) or the sulfonyl compound of formula (IVb') (i" is 2) byvarying the amount of oxidizing agent. An excess of oxidizing agent willfavor the production of a compound where i" is 2.

Alternatively, the compound where i" is 2 may be prepared by oxidizingthe corresponding compound where i" is 1, using the same conditions asdescribed above.

If desired, after completion of these reactions, the hydroxy-protectinggroup represented by R^(41') in any of the compounds of formula (IVa')or (IVb') may be deprotected. This can be accomplished by the well knownmethods described in T. W. Green and P. G. M. Wuts, "Protective Groupsin Organic Synthesis. 2nd Edition", edited by John Wiley and Sons, Inc.,1991, pp. 10.

The invention is further illustrated by the following non-limitingExamples, which illustrate the preparation of compounds of the presentinvention. The subsequent Preparations 1 to 12, 19 to 38 and 41 to 43illustrate the preparation of starting materials for use in theseExamples, and Preparations 13 to 18, 39 and 40 illustrate the use ofcompounds of the present invention to prepare other compounds, leadingultimately to the desired carbapenem compounds.

In the formulae in the Examples, the following abbreviations are usedfor certain groups:

Et: ethyl group

Me: methyl group

PNB: 4-nitrobenzyl group

PNZ: 4-nitrobenzyloxycarbonyl group

TMS: trimethylsilyl group

TBS: t-butyldimethylsilyl group

EXAMPLE 1

(3S,4S)-3[(1R)-1-t-Butyldimethylsilyloxyethyl]-4-[(1R)-(2-pyridylthiocarbonyl)ethyl]azetidin-2-one(Compound No. 1-1) ##STR32## 1(a)Z(O)-2-(1-t-Butyldimethylsilyloxy-1-propenylthio)-pyridine ##STR33##

22.5 ml of a solution containing 1.2 equivalents of butyllithium inhexane were added at room temperature to a solution of 7.5 ml ofhexamethyldisilazane in 50 ml of tetrahydrofuran, and the resultingmixture was stirred for 30 minutes, to prepare 1.2 equivalents oflithium hexamethyldisilazane. The reaction mixture was then cooled to 31κ° C., and 6.25 ml (1.2 equivalents) of hexamethyldisilazane. Thereaction mixture was then cooled to -78° C., and 6.25 ml (1.2equivalents) of hexamethylphosphoric triamide, 8.37 ml (2 equivalents)of triethylamine and 9.60 g(2 equivalents) of t-butyldimethylsilylchloride were added, in that order, followed by a solution of 5 g of2-propionylthiopyridine (prepared as described in Preparation 1) in 10ml of tetrahydrofuran. The reaction mixture was then stirred for 10minutes, after which it was diluted with ethyl acetate. The organiclayer was separated, washed twice with water and then dried overanhydrous magnesium sulfate. The solvent was then removed bydistillation under reduced pressure, and the residue was subjected tofractional distillation, to give 8.4 g (yield 88%) of the titlecompound, boiling at 130° C./0.1 mmHg (13.3 Pa).

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm:

0.09 (6H, singlet);

0.88 (9H, singlet);

1.73 (3H, doublet, J=6.6 Hz);

5.45 (1H, quartet, J=6.6 Hz);

6.97-7.02 (1H, multiplet);

7.32 (1H, doublet, J=8.6 Hz);

7.51-7.57 (1H, multiplet);

8.42 (1H, doublet, J=4 Hz).

This procedure was repeated, except that the hexamethylphoshporictriamide was replaced by the additives shown below. In all cases, theamount of lithium hexamethyldisilazane was 1.2 equivalents, and 2equivalents each of triethylamine and t-butyldimethylsilyl chloride wereemployed. The reaction temperature was -78° C. Using1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone as the additive, andcarrying out the reaction for 10 minutes, the title compound wasobtained in a yield of 88%. Using N,N-dimethylformamide as the additive,and carrying out the reaction for 10 minutes, the title compound wasobtained in a yield of 80%. Using N,N-dimethylacetamide as the additive,and carrying out the reaction for 1 hour, the title compound wasobtained in a yield of 46%.

1(b)(3S,4S)-3[(1R)-1-t-Butyldimethylsilyloxyethyl]-4-[(1R)-(2-pyridylthiocarbonyl)ethyl]azetidin-2-one

163 mg (2 equivalents) of anhydrous zinc chloride (freshly fused) wereadded to a solution of 171 mg ofZ(O)-(3S,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-acetoxyazetidin-2-oneand 337 mg (2 equivalents) of2-(1-t-butyldimethylsilyloxy-1-propenylthio)pyridine [prepared asdescribed in step (a) above] in 15 ml of methylene chloride, and themixture was stirred at a bath temperature of 12° C. for 15 hours. At theend of this time, the reaction mixture was mixed with methylenechloride, and the organic layer was washed three times with water. Itwas then dried over anhydrous magnesium sulfate, and the solvent wasremoved by distillation under reduced pressure. The residue was purifiedby flash chromatography through silica gel, using a 1:1 by volumemixture of cyclohexane and ethyl acetate as the eluent, to give 170 mg(yield 72%) of the title compound having an Rf value of 0.2 and meltingat 109° C.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 1757, 1718, 1696,1564, 3181, 3099.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm:

0.07 (6H, singlet);

0.87 (9H, singlet);

1.19 (3H, doublet, J=5.9 Hz);

1.35 (3H, doublet, J=7.2 Hz);

3.0-3.05 (2H, multiplet);

3.99 (1H, doublet of doublets, J=1.98 & 5.28 Hz);

4.19-4.23 (1H, multiplet);

5.90 (1H, singlet);

7.3-7.32 (1H, multiplet);

7.60 (1H, doublet, J=7.9 Hz);

7.73-7.93 (1H, multiplet);

8.63 (1H, doublet, J=3.9 Hz).

1(c)(3S,4S)-3[(1R)-1-t-Butyldimethylsilyloxyethyl]-4-[(1$)-(2-pyridylthiocarbonyl)ethyl]azetidin-2-one

This provides an alternative method of preparing the same compound aswas prepared in step (b) above.

200 mg (5.7 mmole) ofZ(O)-(3S,4S)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-phenylsulfinylazetidin-2-one(prepared by a procedure similar to that described in Preparation 3)were added to a solution of 160 mg (5.7 mmole)of2-(2-t-butyldimethylsilyloxy-1-propenylthio)pyridine [prepared asdescribed in step (a) above] in 18 ml of methylene chloride, and theresulting mixture was stirred at 15° C. for 4 hours. At the end of thistime, the reaction mixture was mixed with methylene chloride, and theorganic layer was separated and then washed with water and with asaturated aqueous solution of sodium chloride, in that order. Thesolution was then dried over anhydrous magnesium sulfate, and thesolvent was removed by distillation under reduced pressure. Theresulting residue was purified by column chromatography using a 1:1 byvolume mixture of cyclohexane and ethyl acetate as the eluent, to give60 mg (yield 28.7%) of a 18:1 mixture of the title compound and anisomer thereof, in which the methyl group forming part of the ethylgroup at the 4 position of the azetidinone ring is in theα-configuration, instead of the β-configuration.

EXAMPLE 2

(3S,4S)-3-[(1R)-1-t-Butyldimethylsilyloxyethyl]-4-[(1R)-(2-quinolinethiocarbonyl)ethyl]azetidin-2-one(Compound No. 1-5 ##STR34## 2(a)Z(O)-2-(1-t-Butyldimethylsilyloxy-1-propenylthio)quinoline ##STR35##

0.9 ml of a solution containing 1.2 equivalents of butyllithium inhexane was added at room temperature to a solution of 0.3 ml ofhexamethyldisilazane in 10 ml of anhydrous tetrahydrofuran, and theresulting mixture was stirred for 30 minutes. The reaction mixture wasthen cooled to -78° C., and 0.25 ml⁻ (1.2 equivalents) ofhexamethylphosphoric triamide, 0.33 ml (2 equivalents) of triethylamineand 360 mg (2 equivalents) of t-butyldimethylsilyl chloride were added,in that order, to the mixture, followed by 300 mg of2-propionylthioquinoline (prepared as described in Preparation 2). Thereaction mixture was then stirred for 10 minutes, after which it wasmixed with ethyl acetate and the organic layer was separated and washedwith water. The solvent was removed by distillation under reducedpressure, and the resulting residue was purified by flash columnchromatography, using a 10:1 by volume mixture of cyclohexane and ethylacetate as the eluent, to give 320 mg (yield 80%) of the title compoundhaving an Rf value of 0.8.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm:

0.10 (6H, singlet);

0.89 (9H, singlet);

1.73 (3H, doublet, J=6.9 Hz);

5.53 (1H, quartet, J=6.9 Hz);

7.43-7.50 (2H, multiplet);

7.66-7.73 (1H, multiplet);

7.74 (1H, doublet, J=8 Hz);

7.96 (1H, doublet, J=8.6 Hz);

8.00 (1H, doublet, J=8.6 Hz).

2(b)(3S,4S)-3-[(1R)-1-t-Butyldimethylsilyloxyethyl]-4-[(1R)-(2-quinolinethiocarbonyl)ethyl]azetidin-2-one

120 mg (2 equivalents) of anhydrous zinc chloride were added to asolution of 126 mg ofZ(O)-(2S,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-acetoxyazetidin-2-oneand 320 mg (2 equivalents) of2-(1-t-butyldimethylsilyloxy-1-propenylthio)quinoline [prepared asdescribed in step (a) above] in 15 ml of anhydrous methylene chloride,and the resulting mixture was stirred at a bath temperature of 29°-30°C. for 3 hours. At the end of this time, the reaction mixture was mixedwith mthylene chloride. The organic layer was then separated, washedwith water and dried over anhydrous magnesium sulfate. The solvent wasthen removed by distillation under reduced pressure. The resultingresidue was purified by flash chromatography using a 1:1 by volumemixture of cyclohexane and ethyl acetate as the eluent, to give 62 mg(yield 32%) of the title compound having an Rf value of 0.2.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm:

0.01 (6H, singlet);

0.88 (9H, singlet);

1.22 (3H, doublet, J=6 Hz);

1.40 (3H, doublet, J=7.2 Hz);

3.07-3.11 (2H, multiplet);

4.04 (1H, doublet of doublets, J=2 & 5.28 Hz);

4.22-4.26 (1H, multiplet);

5.91 (1H, singlet);

7.63-7.68 (2H, multiplet);

7.7-7.8 (1H, multiplet);

7.87 (1H, doublet, J=8.5 Hz);

8.11 (1H, doublet, J=8.5 Hz);

8.22 (1H, doublet, J=8.58 Hz);

EXAMPLE 3

(3S,4S)-3[(1R)-1-t-Butyldimethylsilyloxyethyl]-4-{(1R)-1-[3-methyl-2-pyridylthiocarbonyl]ethyl}azetidin-2-one(Compound No. 1-2) ##STR36## 3(a)Z(O)-2-(1-t-Butyldimethylsilyloxy-1-propenylthio)-3-methylpyridine##STR37##

15.17 ml (24.3 mmole) of a 1.6 M solution of butyllithium in hexane wereadded dropwise at -78° C. to a solution of 5.59 ml (26.5 mmole) ofhexamethyldisilazane in a mixture of 40 ml of tetrahydrofuran and 4.61ml (26.5 mmole) of hexamethylphosphoric triamide, and then 6.65 g (44.1mmole) of t-bityldimethylsilyl chloride and 9.25 ml (66.3 mmole) oftriethylamine were added to the resulting mixture. The reaction mixturewas then stirred for a further 10 minutes, after which a solution of4.00 g (22.1 mmole) of 2-propionylthio-3-methylpyridine in 10 ml ofanhydrous tetrahydrofuran was added dropwise to the reaction mixture.The mixture was then stirred at -78° C. for 10 minutes, and thetemperature of the reaction mixture was allowed to rise to roomtemperature. A saturated aqueous solution of sodium hydrogencarbonatewas then mixed with the mixture, and the resulting mixture was extractedthree times, each time with 60 ml of pentane. The extract was dried overanhydrous magnesium sulfate, and then the solvent was removed bydistillation under reduced pressure. The resulting residue was purifiedby column chromatography through alumina, using a 5:1 by volume mixtureof hexane and ethyl acetate as the eluent, to give 3.38 g (yield 52%) ofthe title compound as a colorless oil.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm:

0.04 (6H, singlet);

0.85 (9H, singlet);

1.74 (3H, doublet, J=7 Hz);

2.25 (3H, singlet);

5.33 (3H, quartet, J=7 Hz);

6.95 (1H, doublet of doublets, J=7 & 5 Hz);

7.33 (1H, doublet of doublets, J=7 & 1 Hz);

8.37 (1H, doublet of doublets, J=5 & 1 Hz);

3(b)(3S,4S)-3[(1R)-1-t-Butyldimethylsilyloxyethyl]-4-{(1R)-1-[3-methyl-2-pyridylthiocarbonyl]ethyl}azetidin-2-one

190 mg (1.39 mmole) of zinc chloride were added to a solution of 200 mg(0.70 mmole) ofZ(O)-(2S,4S)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-acetoxyazetidin-2-onein 5 ml of methylene chloride, and then a solution of 411 mg of2-(1-t-butyldimethylsilyloxy-1-propenylthio)-3-methylpyridine [preparedas described in step (a) above] in 2 ml of methylene chloride was addedthereto, whilst ice-cooling and under an atmosphere of nitrogen. Theresulting mixture was then stirred at room temperature for 8 hours,after which 50 ml of methylene chloride were added. The organic layerwas washed with ice-water and dried over anhydrous magnesium sulfate,and the solvent was removed by distillation under reduced pressure. Theresulting residue was purified by medium pressure column chromatographythrough silica gel, using a 1:2 by volume mixture of hexane and ethylacetate as the eluent, to give 246 mg (yield 87%) of the title compoundas colorless crystals. A specimen for analysis was recrystallized fromdiisopropyl ether and was found to melt at 120°-122° C.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm:

0.07 (6H, singlet);

0.87 (9H, singlet);

1.20 (3H, doublet, J=6 Hz);

1.35 (3H, doublet, J=7 Hz);

2.36 (3H, singlet);

3.02-3.13 (2H, multiplet);

4.00 (1H, doublet of doublets, J=4 & 2 Hz);

4.20 (1H, multiplet);

5.89 (1H, broad singlet);

7.28 (1H, doublet of doublets, J=8 & 5 Hz);

7.64 (1H, doublet of doublets, J=8 & 1 Hz);

8.50 (1H, doublet of doublets, J=5 & 1 Hz).

EXAMPLE 4

(3S,4S)-3[(1R)-1-t-Butyldimethylsilyloxyethyl]-4-{(1R)-1-[4-methyl-2-pyridylthiocarbonyl]ethyl}azetidin-2-one(Compound No. 1-3) ##STR38## 4(a)Z(O)-2-(1-t-Butyldimethylsilyloxy-1-propenylthio)-4-methylpyridine##STR39##

Following a procedure similar to that described in Example 3(a), butusing 1.51 g (8.33 mmole) of 2-propionylthio-4-methylpyridine, 1.25 g(yield 51%) of the title compound was obtained as a colorless oil.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm:

0.09 (6H, singlet);

0.89 (9H, singlet);

1.74 (3H, doublet, J=7 Hz);

2.30 (3H, singlet);

5.43 (1H, quartet, J=7 Hz);

6.82 (1H, doublet, J=5 Hz);

7.14 (1H, singlet);

8.27 (1H, doublet, J=5 Hz).

4(b)(3S,4S)-3[(1R)-1-t-Butyldimethylsilyloxyethyl]-4-{(1R)-1-[4-methyl-2-pyridylthiocarbonyl]ethyl}azetidin-2-one

Following a procedure similar to that described in Example 3(b), butusing 500 mg (1.74 mmole) ofZ(O)-(3S,4S)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-acetoxyazetidin-2-one,1.03 g (3.49 mmole) of2-(1-t-butyldimethylsilyloxy-1-propenylthio-4-methylpyridine [preparedas described in step (a) above] and 474 mg (3.48 mmole) of zincchloride, 502 mg (yield 71%) of the title compound were obtained ascolorless crystals. A specimen for analysis was recrystallized fromdiisopropyl ether and melted at 123°-125° C.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm:

0.07 (6H, singlet);

0.87 (9H, singlet);

1.19 (3H, doublet, J=6 Hz);

1.35 (3H, doublet, J=7 Hz);

2.40 (3H, singlet);

2.95-3.10 (2H, multiplet);

3.98 (1H, doublet of doublets, J=5 & 2 Hz);

4.21 (1H, multiplet);

5.92 (1H, broad);

7.13 (1H, doublet of doublets, J=5 & 1 Hz);

7.42 (1H, doublet, J=1 Hz);

8.48 (1H, doublet, J=5 Hz).

EXAMPLE 5

(3S,4S)-3[(1R)-1-t-Butyldimethylsilyloxyethyl]-4-{(1R)-1-[5-methyl-2-pyridylthiocarbonyl]ethyl}azetidin-2-one(Compound No. 1 -4) ##STR40## 5(a)Z(O)-2-(1-t-Butyldimethylsilyloxy-1-propenylthio)-5-methylpyridine##STR41##

Following a procedure similar to that described in Example 3(a), butusing 1.80 g (9.93 mmole) of 2-propionylthio-5-methylpyridine, 1.50 g(yield 51%) of the title compound was obtained as a colorless oil.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃). δ ppm:

0.09 (6H, singlet);

0.88 (9H, singlet);

1.72 (3H, doublet, J=7 Hz);

2.27 (3H, singlet);

5.42 (1H, quartet, J=7 Hz);

7.22 (1H, doublet, J=8 Hz);

7.36 (1H, doublet of doublets, J=8 & 2 Hz);

8.26 (1H, doublet, J=2 Hz).

5(b)(3S,4S)-3[(1R)-1-t-Butyldimethylsilyloxyethyl]-4-{(1R)-1-[5-methyl-2-pyridylthiocarbonyl]ethyl}azetidin-2-one

Following a procedure similar to that described in Example 3(b), butusing 500 mg (1.74 mmole) ofZ(O)-(3S,4S)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-acetoxyazetidin-2-one,1.03 g (3.49 mmole) of2-(1-t-butyldimethylsilyloxy-1-propenylthio)-5-methylpyridine [preparedas described in step (a) above] and 474 mg (3.48 mmole) of zincchloride, 583 mg (yield 82%) of the title compound were obtained ascolorless crystals. A specimen for analysis was recrystallized fromdiisopropyl ether and melted at 86°-88° C.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm:

0.07 (6H, singlet);

0.87 (9H, singlet);

1.19 (3H, doublet, J=6 Hz);

1.34 (3H, doublet, J=7 Hz);

2.37 (3H, singlet);

2.95-3.08 (2H, multiplet);

3.98 (1H, doublet of doublets, J=5 & 2 Hz);

4.21 (1H, multiplet);

5.90 (1H, broad singlet);

7.46 (1H, doublet, J=8 Hz);

7.56 (1H, doublet of doublets, J=8 & 2 Hz);

8.47 (1H, doublet, J=2 Hz).

EXAMPLE 6

S-2-Diethylcarbamoylphenyl2(R)-{(3S,4S)-3-[1-(R)-(t-butyldimethylsilyloxy)ethyl]-2-oxo-4-azetidinyl}thiopropionateand its 2(S)-isomer (Compound No. 2-2) ##STR42##

330 mg (2.42 mmole) of anhydrous zinc chloride were added to a solutionof 911 mg (2.40 mmole) of1-t-butyldimethylsilyloxy-1-(2-diethylcarbamoyl)phenylthio-1-propene(prepared as described in Preparation 19) and 347 mg (1.21 mmole) of(3R,4R)-3-[1(R)-(t-butyldimethylsilyloxy)ethyl]-4-acetoxy-2-azetidinonein 12 ml of methylene chloride, and the resulting mixture was stirred atroom temperature for 2 hours. At the end of this time, the reactionmixture was diluted with ethyl acetate and the mixture was washed withwater and dried over anhydrous magnesium sulfate. The solvent was thenremoved by distillation under reduced pressure. The resulting residuewas purified by chromatography through a Lobar column, using a 1:1 byvolume mixture of hexane and ethyl acetate as the eluent, to give 61 mg(yield 10%) of the 2S-isomer of the title compound, melting at125°-126.5° C. (after recrystallization from a mixture of hexane andethyl acetate), and 487 mg (yield 82%) of the 2R-isomer of the titlecompound, melting at 130.5°-132° C. (after recrystallization fromdiisopropyl ether).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹

(2S-isomer):

3182, 1765, 1711, 1629, 953, 774;

(2R-isomer):

3086, 1762, 1700, 1637, 965, 829.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm:

(2S-isomer):

0.06 (3H, singlet);

0.07 (3H, singlet);

0.87 (9H, singlet);

1.05 (3H, triplet, J=7 Hz);

1.26 (3H, doublet, J=6 Hz);

1.26 (3H, triplet, J=7 Hz);

1.28 (3H, doublet, J=7 Hz);

2.71-2.83 (2H, multiplet);

3.00-3.21 (2H, nonet-like, J=7 Hz);

3.35-3.80 (2H, broad);

3.63 (1H, doublet, J=9 Hz);

4.14 (1H, quintet, J=6 Hz);

7.00-7.30 (1H, broad singlet);

7.30-7.35 (1H, multiplet);

7.42-7.53 (3H, multiplet);

(2R-isomer):

0.08 (6H, singlet);

0.87 (9H, singlet);

1.03 (3H, triplet, J=7 Hz);

1.21 (3H, doublet, J=6 Hz);

1.25 (3H, triplet, J=7 Hz);

1.29 (3H, doublet, J=7 Hz);

2.96-3.15 (4H, multiplet);

3.20-3.85 (2H, broad);

3.96 (1H, doublet of doublets, J=2 & 4 Hz);

4.19 (1H, quintet, J=6 Hz);

5.90-6.10 (1H, broad singlet);

7.30-7.35 (1H, multiplet);

7.41-7.51 (3H, multiplet).

Mass spectrum (m/z): (2R- and 2S-isomers) 492 (M⁺, C₂₅ H₄₀ N₂ O₄ SSi).

Elemental analysis:

Calculated for C₂₅ H₄₀ N₂ O₄ SSi: C, 60.94%, H, 8.18%; N, 5.69%; S,6.51%.

Found, 2S-isomer: C, 60.72%; H, 8.01%; N, 5.70%; S, 6.57%.

Found, 2R-isomer: C, 60.85%; H, 8.10%; N, 5.62%; S, 6.50%.

EXAMPLES 7 to 17

Following a similar procedure to that described in Example 6, thefollowing compounds were also synthesized.

EXAMPLE 7

S-2-Dimethylcarbamoylphenyl2(R)-{(3S,4S)-3-[1(R)-(t-butyldimethylsilyloxy)ethyl]-2-oxo-4-azetidinyl}thiopropionate(Compound No. 2-1) ##STR43##

The yield of the 2R-isomer was 79%, and the ratio of the yields of2R-isomer to 2S-isomer was 4.9:1.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm:

0.08 (6H, singlet);

0.88 (9H, singlet);

1.21 (3H, doublet, J=6 Hz);

1.29 (3H, doublet, J=7 Hz);

2.79 (3H, singlet);

2.96-3.08 (2H, multiplet);

3.10 (3H, singlet);

3.94 (1H, doublet of doublets, J=2 & 5 Hz);

4.19 (1H, doublet of quartets, J=5 & 6 Hz);

6.10-6.20 (1H, broad singlet);

7.31-7.36 (1H, multiplet);

7.40-7.70 (3H, multiplet).

The 2R-isomer was in the form of needle-like crystals, melting at99°-101° C. (after recrystallization from a mixture of ethyl acetate andhexane).

EXAMPLE 8

S-2-Dipropylcarbamoylphenyl2(R)-{(3S,4S)-3-[1(R)-(t-butyldimethylsilyloxy)ethyl]-2-oxo-4-acetidinyl}-thiopropionate(Compound No. 2-3) ##STR44##

The yield of the 2R-isomer was 74%, and the ratio of the yields of2R-isomer to 2S-isomer was 3.5:1.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm:

0.08 (6H, singlet);

0.72 (3H, triplet, J=7 Hz);

0.88 (9H, singlet);

1.00 (3H, triplet, J=7 Hz);

1.22 (3H, doublet, J=6 Hz);

120-1.40 (3H, broad);

1.46 (2H, sextet, J=7 Hz);

1.70 (2H, sextet, J=7 Hz);

2.91-3.06 (2H, multiplet);

3.10-3.80 (2H, broad);

3.96 (2H, doublet of doublets, J=2 & 4 Hz);

4.19 (1H, doublet of quartets, J=5 & 6 Hz);

5.90-6.20 (1H, broad singlet);

7.92-7.35 (1H, multiplier);

7.40-7.52 (3H, multiplet).

The 2R-isomer was in the form of needle-like crystals, melting at112°-113° C. (after recrystallization from a mixture of ethyl acetateand hexane).

EXAMPLE 9

S-2-Diisobutylcarbamoylphenyl2(R)-{(3S,4S)-3-[1(R)-(t-butyldimethylsilyloxy)ethyl]-2-oxo-4-azetidinyl}thiopropionate(Compound No. 2-6) ##STR45##

The yield of the 2R-isomer was 70%, and the ratio of the yields of2R-isomer to 2S-isomer was 4.6:1.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm:

0.08 (6H, singlet);

0.74 (6H, doublet, J=7 Hz);

0.87 (9H, singlet);

1.02 (6H, doublet, J=7 Hz);

1.21 (3H, doublet, J=6 Hz);

1.20-1.40 (3H, broad);

1.81 (1H, septet, J=7 Hz);

2.12 (1H, septet, J=7 Hz);

2.80-3.06 (4H, multiplet);

3.20-3.57 (2H, broad);

3.92-4.05 (1H, broad singlet);

4.13-4.28 (1H, broad);

5.95-6.15 (1H, broad);

7.29-7.35 (1H, multiplet);

7.42-7.50 (3H, multiplet).

The 2R-isomer was in the form of needle-like crystals, melting at144°-146° C. (after recrystallization from a mixture of ethyl acetateand hexane).

EXAMPLE 10

S-2-(N-Methyl-N-phenylcarbamoyl)phenyl2(R)-{(3S,4S)-3-[1(R)-(t-butyldimethylsilyloxy)ethyl]-2-oxo-4-azetidinyl}thiopropionate(Compound No. 2-16) ##STR46##

The yield of the 2R-isomer was 64%, and the ratio of the yields of2R-isomer to 2S-isomer was 2.6:1.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm:

0.08 & 0.09 (together 6H, each singlet);

0.88 (9H, singlet);

1.23 (3H, doublet, J=6 Hz);

1.34 (3H, doublet, J=7 Hz);

3.01-3.12 (2H, multiplet);

3.49 (3H, singlet);

4.00-4.08 (1H, broad singlet);

4.20 (1H, doublet of quartets, J=6 & 6 Hz);

6.05-6.20 (1H, broad singlet);

6.95-7.63 (9H, multiplet).

The 2R-isomer was in the form of needle-like crystals, melting at158°-159.5° C. (after recrystallization from a mixture of ethyl acetateand hexane).

EXAMPLE 11

S-2-(1-Pyrrolidinylcarbonyl)phenyl2(R)-{(3S,4S)-3-[1(R)-(t-butyldimethylsilyloxy)ethyl]-2-oxo-4-azetidinyl}thiopropionate(Compound No. 3-3) ##STR47##

The yield of the 2R-isomer was 85%, and the ratio of the yields of2R-isomer to 2S-isomer was 7.1:1.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm:

0.08 (6H, singlet);

0.88 (9H, singlet);

1.21 (3H, doublet, J=6 Hz);

1.29 (3H, doublet, J=7 Hz);

1.75-2.00 (4H, multiplet);

2.95-3.06 (2H, multiplet);

3.18 (2H, triplet, J=7 Hz);

3.60 (2H, triplet, J=7 Hz);

3.96 (1H, doublet of doublets, J=2 & 4 Hz);

4.20 (1H, doublet of quartets, J=5 & 6 Hz);

6.10-6.25 (1H, broad singlet);

7.37-7.53 (4H, multiplet).

The 2R-isomer was in the form of a foam-like substance.

EXAMPLE 12

S-2-(1-Piperidylcarbonyl)phenyl2(R)-{(3S,4S)-3-[1(R)-(t-butyldimethylsilyloxy)ethyl]-2-oxo-4-azetidinyl}thiopropionate(Compound No. 3-4) ##STR48##

The yield of the 2R-isomer was 75%, and the ratio of the yields of2R-isomer to 2S-isomer was 4.8:1.

nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm:

0.07 & 0.08 (together 6H, two singlets);

0.87 & 0.88 (together 9H, two singlets);

1.16-1.25 (3H, multiplet);

1.28 & 1.33 (together 3H, two doublets, J=7 & 7 Hz);

1.37-1.52 (2H, broad);

1.54-1.77 (4H, broad);

2.95-3.26 (4H, multiplet);

3.47-3.60 (1H, broad);

3.80-3.95 (1H, broad);

3.97 (1H, doublet of doublets, J=2 & 4 Hz);

4.12-4.26 (1H, broad);

6.00-6.16 (1H, broad);

7.26-7.52 (4H, multiplet).

The 2R-isomer was in the form of a glassy substance.

EXAMPLE 13

S-2-Morpholinocarbonylphenyl2(R)-{(3S,4S)-3-[1(R)-(t-butyldimethylsilyloxy)ethyl]-2-oxo-4-azetidinyl}thiopropionate(Compound No. 3-8) ##STR49##

The yield of the 2R-isomer was 83%, and the ratio of the yields of2R-isomer to 2S-isomer was 7.9:1.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm:

0.08 (6H, singlet);

0.88 (9H, singlet);

1.21 (3H, doublet, J=7 Hz);

1.22-1.38 (3H, multiplet);

2.97-3.08 (2H, multiplet);

3.12-3.32 (2H, multiplet);

3.50-3.60 (2H, multiplet);

3.70-3.84 (4H, broad);

3.93-4.01 (1H, broad singlet);

4.19 (1H, doublet of quartets, J=5 & 5 Hz);

5.90-6.10 (1H, broad);

7.20-7.38 (1H, multiplet);

7.42-7.55 (3H, multiplet).

The 2R-isomer was in the form of a glassy substance.

EXAMPLE 14

S-2-(1-Azepinylcarbonyl)phenyl2(R)-{(3S,4S)-3-[1(R)-(t-butyldimethylsilyloxy)ethyl]-2-oxo-4-azetidinyl}thiopropionate(Compound No. 3-5) ##STR50##

The yield of the 2R-isomer was 87%, and the ratio of the yields of2R-isomer to 2S-isomer was 9.5:1.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm:

0.08 (6H, singlet);

0.88 (9H, singlet);

1.22 (3H, doublet, J=6 Hz);

1.20-1.40 (3H, broad);

1.50-1.96 (8H, broad);

2.97-3.10 (2H, multiplet);

3.06-3.32 (2H, broad);

3.40-3.90 (2H, broad);

3.96 (1H, doublet of doublets, J=2 & 4 Hz);

4.20 (1H, doublet of quartets, J=6 & 6 Hz);

6.05-6.25 (1H, broad);

7.30-7.37 (1H, multiplet);

7.42-7.52 (3H, multiplet).

The 2R-isomer was in the form of a glassy substance.

EXAMPLE 15

S-2-Diethylcarbamoyl-6-methylphenyl2(R)-{(3S,4S)-3-[1(R)-(t-butyldimethylsilyloxy)ethyl]-2-oxo-4-azetidinyl}thiopropionate(Compound No. 2-40) ##STR51##

The yield of the 2R-isomer was 88%, and the ratio of the yields of2R-isomer to 2S-isomer was 12.3:1.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm:

0.06 (3H, singlet);

0.86 (9/2H, singlet);

0.89 (9/2H, singlet);

1.02 (3H, triplet, J=7 Hz);

1.19-1.29 (7.5H, multiplet);

1.35 (1.5H, doublet, J=7 Hz);

2.35 (3H, singlet);

2.92-3.16 (4H, multiplet);

3.28-3.41 (1H, multiplet);

3.74 (1H, doublet of quartets, J=14 & 7 Hz);

3.95-4.00 (1H, multiplet);

4.17 (1H, quintet, J=6 Hz);

6.00-6.30 (1H, broad singlet);

7.14 (1H, doublet of doublets, J=3 & 6 Hz);

7.34-7.41 (2H, multiplet).

The 2R-isomer was in the form of needle-like crystals, melting at150°-150.5° C. (after recrystallization from diisopropyl ether).

EXAMPLE 16

S-2-[Diethyl(thiocarbamoyl)]-6-methylphenyl2(R)-{(3S,4S)-3-[1(R)-(t-butyldimethylsilyloxy)ethyl]-2-oxo-4-azetidinyl}thiopropionate(Compound No. 2-63) ##STR52##

The yield of the 2R-isomer was 81%, and the ratio of the yields of2R-isomer to 2S-isomer was 4.8:1.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm:

0.09 (6H, singlet);

0.89 (9H, singlet);

1.09 (3H, triplet, J=7 Hz);

1.22 (3H, doublet, J=6 Hz);

1.26 (3H, doublet, J=7 Hz);

1.38 (3H, triplet, J=7 Hz);

2.96-3.06 (2H, multiplet);

3.20 (1H, doublet of quartets, J=14 & 7 Hz);

3.36 (1H, doublet of quartets, J=14 & 7 Hz);

3.76 (1H, doublet of quartets, J=14 & 7 Hz);

3.97 (1H, doublet of doublets, J=2 & 5 Hz);

4.20 (1H, doublet of quartets, J=5 & 6 Hz);

4.46 (1H, doublet of quartets, J=14 & 7 Hz);

7.22-7.26 (1H, multiplet);

7.33-7.46 (3H, multiplet).

The 2R-isomer was in the form of needle-like crystals, melting at163°-165° C. (after recrystallization from a mixture of ethyl acetateand hexane).

EXAMPLE 17

S-2-Diethylcarbamoylphenyl2(R)-{(3S,4S)-3-[1(R)-(t-butyldimethylsilyloxy)ethyl]-2-oxo-4-azetidinyl}propionate(Compound No. 2-56) ##STR53##

The yield of the 2R-isomer was 61%, and the ratio of the yields of2R-isomer to 2S-isomer was 6.8:1.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm:

0.09 (6H, singlet);

0.88 (9H, singlet);

1.10 (3H, triplet, J=7 Hz);

1.22 (3H, triplet, J=7 Hz);

1.25 (3H, doublet, J=6 Hz);

1.32 (3 Hz, doublet, J=7 Hz);

2.95 (1H, doublet of quartets, J=4 & 7 Hz);

3.00 (1H, doublet, j=6 Hz);

3.22 (2H, quartet, J=7 Hz);

3.42-3.63 (1H, multiplet);

4.08-4.16 (1H, multiplet);

4.18 (1H, quintet, J=6 Hz);

6.45 (1H, broad singlet);

7.17 (1H, doublet, J=8 Hz);

7.26-7.28 (2H, multiplet);

7.38-7.43 (1H, multiplet).

The 2R-isomer was in the form of a glassy substance.

PREPARATION 1 2-Propionylthiopyridine

15.6 ml (1.2 equivalents) of propionyl chloride were slowly added atroom temperature to a solution of 20 g of 2-pyridinethiol and 25.1 ml(1.2 equivalents) of triethylamine in 200 ml of anhydrous methylenechloride, and the resulting mixture was stirred for 1 hour. At the endof this time, the solvent was removed by distillation under reducedpressure, and the resulting residue was mixed with ethyl acetate. Theorganic solution thus obtained was washed twice with a dilute aqueoussolution of sodium hydrogencarbonate and then with water. The organiclayer was separated and then dried over anhydrous magnesium sulfate,after which the solvent was removed by distillation under reducedpressure. The residue was subjected to fractional distillation in vacuo,to give 27 g (yield 90%) of the title compound, boiling at 93° C./0.05mmHg (6.7 Pa).

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm:

1.24 (3H, doublet, J=7.5 Hz);

2.74 (2H, quartet, J=7.5 Hz);

7.30-7.63 (1H, multiplet);

7.62 (1H, doublet, J=7.9 Hz);

7.70-7.76 (1H, multiplet);

8.61-8.63 (1H, multiplet);

PREPARATION 2 2-Propionylthioquinoline

480 mg (1.2 equivalents) of propionyl chloride were added, whilstice-cooling, to a solution of 1 g of 2-quinolinethiol and 0.83 ml (1.2equivalents) of triethylamine in 20 ml of anhydrous methylene chloride,and the resulting mixture was stirred for 30 minutes. At the end of thistime, the solvent was removed by distillation under reduced pressure,and the resulting residue was mixed with ethyl acetate. This mixture waswashed twice with a dilute aqueous solution of sodium hydrogencarbonateand was then washed with water. The organic layer was separated anddried over anhydrous magnesium sulfate and the solvent was removed bydistillation under reduced pressure. The residue was purified by flashchromatography through silica gel, using a 1:1 by volume mixture ofcyclohexane and ethyl acetate as the eluent, to give 600 mg of the titlecompound having an Rf value of 0.4.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm:

1.27 (3H, triplet, J=7.2 Hz);

2.79 (2H, quartet, J=7.2 Hz);

7.53-7.61 (1H, multiplet);

7.67-7.76 (2H, multiplet);

7.49 (1H, doublet, J=7.9 Hz);

8.09 (1H, doublet, J=8.5 Hz);

8.19 (1H, doublet, J=8.5 Hz).

PREPARATION 3

(3S,4R)-3-[(1R)-1-t-Butyldimethylsilyloxyethyl]-4-phenylsulfinylazetidin-2-one##STR54## 3(i)(3S,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-phenylthio-2-azetidinone

0.7 g of sodium thiophenolate was added, whilst ice-cooling, to asolution of 2 g of(3S,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-acetoxyazetidin-2-onein 20 ml of ethanol, and the resulting mixture was stirred at roomtemperature for 3 hours. At the end of this time, the reaction mixturewas mixed with 50 ml of ethyl acetate, and the organic layer wasseparated and washed with water, with a saturated aqueous solution ofsodium hydrogencarbonate and with water, in that order. It was thendried over anhydrous magnesium under reduced pressure, to give 2 g ofthe title compound as colorless crystals, melting at 110°-112.5° C.

Rf=0.5 (thin layer chromatography through silica gel; developingsolvent: a 3:1 by volume mixture of cyclohexane and ethyl acetate).

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm:

0.06 (6H, singlet);

0.87 (9H, singlet);

1.20 (3H, doublet, J=6.6 Hz);

3.02-3.04 (1H, multiplet);

4.18-4.26 (1H, multiplet);

5.07 (1H, doublet, J=2.6 Hz);

6.05 (1H, singlet);

7.33-7.48 (5H, multiplet).

3(ii)(3S,4R)-3-[(1R)-1-t-Butyldimethylsilyloxyethyl]-4-phenylsulfinylazetidin-2-one

1.5 g of 3-chloroperoxybenzoic acid was added, whilst ice-cooling, to asolution of 2 g of(3S,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-phenylthio-2-azetidinone[prepared as described in step (i) above] in 30 ml of methylenechloride, and the resulting mixture was stirred at room temperature for6 hours. At the end of this time, the reaction mixture was mixed with 30ml of methylene chloride, and the organic layer was separated and washedwith water, with a saturated aqueous solution of sodiumhydrogencarbonate and again with water, in that order. It was then driedover anhydrous magnesium sulfate, and the solvent was removed bydistillation under reduced pressure. The resulting residue was purifiedby flash chromatography, using a 1:1 by volume mixture of cyclohexaneand ethyl acetate as the eluent, to give 1.9 g of the title compoundconsisting of two diastereomers, differing in the configuration of thesulfoxide group, as colorless crystals, melting at 65°-70° C.

Rf=0.4 (developing solvent: a 1:1 by volume mixture of cyclohexane andethyl acetate).

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz, δ ppm:

0.02-0.04 (6H, multiplet);

0.82-0.84 (9H, multiplet);

1.43 (3H, singlet);

3.35-3.36 (0.4H, multiplet);

3.51 (0.6H, singlet);

4.16-4.25 (1H, multiplet);

4.53 (1H, singlet);

6.57 (0.4H, singlet);

6.69 (0.6H, singlet);

7.51-7.72 (5H, multiplet).

PREPARATION 4 2-Hydroxy-3-methylpyridine

A solution of 2.30 g (33.3 mmole) of sodium nitrite in 5 ml of water wasadded dropwise at room temperature to a solution of 3.60 g (33.3 mmole)of 2-amino-3-picoline in a mixture of 65 ml of water and 4 ml ofconcentrated sulfuric acid, and the resulting mixture was stirred atroom temperature for 2 hours. At the end of this time, the pH of thereaction mixture was adjusted to a value of 7 by the addition of sodiumcarbonate, and the water was removed by distillation under reducedpressure. The mixture was then extracted three times, each time with 80ml of warm ethanol. The extract was then freed from the ethanol bydistillation under reduced pressure, and the resulting residue wasrecrystallized from ethyl acetate, to give 3.38 g (yield 93%) of thetitle compound as colorless crystals, melting at 137°-139° C.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm:

2.18 (3H, singlet);

6.22 (1H, doublet of doublets, J=7 & 7 Hz);

7.3-7.4 (2H, multiplet);

13.14 (1H, singlet).

PREPARATION 5 2-Hydroxy-4-methylpyridine

Following a procedure similar to that described in Preparation 4, butusing 3.60 g (33.3 mmole) of 2-amino-4-picoline, 2.32 g (yield 64%) ofthe title compound were obtained as colorless crystals, melting at121°-123° C.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm:

2.28 (3H, singlet);

6.14 (1H, doublet, J=6 Hz);

6.39 (1H, singlet);

7.27 (1H, doublet, J=6 Hz);

13.24 (1H, singlet).

PREPARATION 6 2-Hydroxy-5-methylpyridine

Following a procedure similar to that described in Preparation 4, butusing 3.60 g (33.3 mmole) of 2-amino-5-picoline, 2.56 g (yield 71%) ofthe title compound were obtained as colorless crystals, melting at175°-177° C.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm:

2.10 (3H, singlet);

6.53 (1H, doublet, J=9 Hz);

7.16 (1H, broad singlet);

7.33 (1H, doublet of doublets, J=9 & 3 Hz);

13.35 (1H, singlet).

PREPARATION 7 2-Mercapto-3-methylpyridine

A mixture of 2.00 g (18.3 mmole) of 2-hydroxy-3-methylpyridine (preparedas described in Preparation 4) and 2.17 g (9.76 mmole) of phosphoruspentasulfide was heated at 160° C. for 4 hours. At the end of this time,the reaction mixture was diluted with 200 ml of water, and the pH of themixture was adjusted to a value of 6 by the addition of potassiumcarbonate. The mixture was then extracted twice, each time with 100 mlof chloroform. The extract was washed with a saturated aqueous solutionof sodium chloride and dried over anhydrous magnesium sulfate. Thesolvent was then removed by distillation under reduced pressure. Theresulting residue was recrystallized from benzene to give 2.15 g (yield94%) of the title compound as yellow crystals, melting at 163°-165° C.

.sup. H Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm:

2.44 (3H, singlet);

6.74 (1H, doublet of doublets, J=7 & 7 Hz);

7.45 (1H, broad doublet, J=7 Hz);

7.53 (1H, broad doublet, J=7 Hz);

13.82 (1H, singlet).

Mass Spectrum m/e: 125 (M⁺)

PREPARATION 8 2-Mercapto-4-methylpyridine

Following a procedure similar to that described in Preparation 7, butusing 2.26 g (20.7 mmole) of 2-hydroxy-4-methylpyridine (prepared asdescribed in Preparation 5), 2.01 g (yield 78%) of the title compoundwere obtained as yellow crystals, melting at 174°-176° C.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm:

2.27 (3H, singlet);

6.63 (1H, doublet, J=6 Hz);

7.42 (1H, singlet);

7.51 (1H, doublet, J=6 Hz);

13.69 (1H, singlet).

PREPARATION 9 2-Mercapto-5-methylpyridine

Following a procedure similar to that described in Preparation 7, butusing 2.48 g (22.7 mmole) of 2-hydroxy-5-methylpyridine (prepared asdescribed in Preparation 6), 2.43 g (yield 86%) of the title compoundwere obtained as yellow crystals, melting at 178°-181° C.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm:

2.20 (3H, singlet);

7.26 (1H, doublet of doublets, J=9 & 2 Hz);

7.43 (1H, broad singlet);

7.49 (1H, doublet, J=9 Hz);

13.89 (1H, singlet).

PREPARATION 10 2-Propionylthio-3-methylpyridine

1.21 ml (13.9 mmole) of propionyl chloride were added dropwise, whilstice-cooling and under an atmosphere of nitrogen, to a solution of 1.46 g(11.7 mmole) of 2-mercapto-3-methylpyridine (prepared as described inPreparation7) and 1.94 ml (13.9 mmole) of triethylamine in 15 ml ofmethylene chloride, and the resulting mixture was stirred for 1 hour. Atthe end of this time, the reaction mixture was mixed with 50 ml ofmethylene chloride, and the mixture was washed with a saturated aqueoussolution of sodium hydrogencarbonate. It was then dried over anhydrousmagnesium sulfate, and the solvent was removed by distillation underreduced pressure. The residue was purified by medium pressure columnchromatography through silica gel, using a 5:1 by volume mixture ofhexane and ethyl acetate as the eluent, to give 1.89 g (yield 89%) ofthe title compound as a light yellow oil.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm:

1.24 (3H, triplet, J=7 Hz);

2.37 (3H, singlet);

2.73 (2H, quartet, J=7 Hz);

7.25 (1H, doublet of doublets, J=8 & 5 Hz);

7.61 (1H, doublet, J=8 Hz);

8.48 (1H, doublet, J=5 Hz).

Mass Spectrum m/e: 182 (M⁺ +H)

PREPARATION 11 2-Propionylthio-4-methylpyridine

Following a procedure similar to that described in Preparation 10, butusing 1.20 g (9.59 mmole) of 2-mercapto-4-methylpyridine (prepared asdescribed in Preparation 8), 1.62 g (yield 93%) of the title compoundwere obtained as a light yellow oil.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm:

1.24 (3H, triplet, J=7 Hz);

2.38 (3H, singlet);

2.72 (2H, quartet, J=7 Hz);

7.10 (1H, doublet, J=5 Hz);

7.44 (1H, singlet);

8.47 (1H, doublet, J=5 Hz).

PREPARATION 12 2-Propionylthio-5-methylpyridine

Following a procedure similar to that described in Preparation 10, butusing 1.40 g (11.2 mmole) of 2-mercapto-5-methylpyridine (prepared asdescribed in Preparation 9), 1.97 g (yield 97%) of the title compoundwere obtained as a light yellow oil.

¹ H Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm:

1.23 (3H, triplet, J=7 Hz);

2.35 (3H, singlet);

2.71 (2H, quartet, J=7 Hz);

7.47 (1H, doublet, J=8 Hz);

7.54 (1H, doublet of doublets, J=8 & 2 Hz);

8.45 (1H, doublet, J=2 Hz).

Mass Spectrum m/e: 181 (M⁺)

PREPARATION 13

(3S,4S)-3-[(1R)-1-t-Butyldimethyloxyethyl]-4-{2(S)-[4-(2-p-nitrobenzyloxycarbonyloxyethyl)piperazin-1-ylcarbonyl]-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-4(S)-yl]thiocarbonylethyl}azetidin-2-one##STR55##

0.75 ml (5.38 mmole) of triethylamine was added, whilst ice-cooling andunder an atmosphere of nitrogen, to a solution of 1.76 g (4.47 mmole) of(3S,4S)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-[1(R)-(2-pyridylthiocarbonyl)ethyl]azetidin-2-oneprepared as described in Example 1) and 2.79 g (4.52 mmole) of(2S,4S)-2-{4-[2-(p-nitrobenzyloxycarbonyloxy)ethyl]-1-piperazinylcarbonyl}-4-mercapto-1-(p-nitrobenzyloxycarbonyl)pyrrolidinein 40 ml of methylene chloride, and the resulting mixture was stirred atroom temperature for 7 hours. At the end of this time, the reactionmixture was mixed with 100 ml of methylene chloride, and the organicmixture was then washed twice, each time with 50 ml of a cooled 1Naqueous solution of sodium hydroxide, after which it was washed with asaturated aqueous solution of sodium chloride. It was then dried overanhydrous magnesium sulfate, and the solvent was removed by distillationunder reduced pressure. The resulting residue was recrystallized from 40ml of ethyl acetate, to give 3.03 g (yield 75%) of the title compound ascolorless crystals, melting at 141°-143° C.

PREPARATION 14

(3S,4S)-3-[(1R)-1-Hydroxyethyl]-4-{2(S)-[4-(2-p-nitrobenzyloxycarbonyloxyethyl)piperazin-1-ylcarbonyl]-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-4(S)-yl]-thiocarbonylethyl}azetidin-2-one##STR56##

24 ml of 3N aqueous hydrochloric acid were added dropwise, whilstice-cooling, to a solution of 8.1 g of(3S,4S)-3-[(1R)-1-t-butyldimethyloxyethyl]-4-{2(S)-[4-(2-p-nitrobenzyloxycarbonyloxyethyl)piperazin-1-ylcarbonyl]-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-4(S)-yl]thiocarbonylethyl}azetidin-2-one (prepared asdescribed in Preparation 13) in 80 ml of methanol, after which theresulting mixture was stirred at the same temperature for 30 minutes andthen allowed to stand overnight in a refrigerator. At the end of thistime, the pH of the reaction mixture was adjusted to a value of 5 to 6by the addition of sodium hydrogencarbonate, whilst ice-cooling. Themixture was then concentrated by evaporation under reduced pressure, andthe concentrate was mixed with a small amount of water and extractedwith ethyl acetate. The aqueous layer was separated, saturated withsodium chloride and extracted with ethyl acetate. The extracts werecombined and the solvent was then removed by distillation under reducedpressure. The resulting residue was purified by flash chromatographythrough 150 g of silica gel (Merck Art No. 9385) using a gradientelution method with mixtures of ethyl acetate and methanol ranging from20:1 to 10:1 by volume as the eluent, to give 5.9 g of the titlecompound as a colorless foam.

Infrared Absorption Spectrum (CHCl₃), ν_(max) cm⁻¹ : 1752, 1710, 1650,1607, 1522, 1443, 1405, 1347, 1263.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm:

1.27 (3H, doublet, J=6.83 Hz);

1.28 (3H, doublet, J=6.35 Hz);

1.82-1.99 (1H, multiplet);

2.10-2.18 (1H, multiplet);

2.40-2.95 (7H, multiplet);

3.03 (1H, doublet of doublets, J=1.95 & 6.35 Hz);

3.37-3.80 (5H, multiplet);

3.78 (1H, doublet of doublets, J=1.95 & 6.84 Hz);

3.95-4.48 (6H, multiplet);

4.68 & 4.73 (together 1H, two triplets, J=8.06 & 7.33 Hz);

5.06 & 5.32 (together 1H, two doublets, J=13.43 & 13.43 Hz);

5.21 (1H, singlet);

5.26 (2H, singlet);

5.99 (1H, broad singlet);

7.45 & 7.50 (together 2H, two doublets, J=8.30 & 8.79 Hz);

7.56 ((2H, doublet, J=8.79 Hz);

8.18-8.26 (4H, multiplet).

PREPARATION 15

(3S,4S)-3-[(1R)-1-(Trimethylsilyloxy)ethyl]-4-{2(S)-[4-(2-p-nitrobenzyloxycarbonyloxyethyl)piperazin-1-ylcarbonyl]-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-4(S)-yl]-thiocarbonylethyl}azetidin-2-one##STR57##

3.6 g of triethylamine and then 2.76 g of chlorotrimethylsilane wereadded dropwise, whilst ice-cooling and under a stream of nitrogen, to asolution of 4.0 g of(3S,4S)-3-[(1R)-1-hydroxyethyl]-4-{2(S)-[4-(2-p-nitrobenzyloxycarbonyloxyethyl)-piperazin-1-ylcarbonyl]-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-4(S)-yl]-thiocarbonylethyl}azetidin-2-one(prepared as described in Preparation 14) in 40 ml of methylenechloride, and the resulting mixture was stirred at room temperature for20 minutes. The reaction mixture was then again cooled, and 25 ml ofmethanol and 3.3 g of silica gel (Merck Art. No. 7734) were added to themixture, after which it was stirred at room temperature for 3 hours. Themixture was then concentrated by evaporation under reduced pressure, andthe concentrate was mixed with water and extracted with ethyl acetate.The extract was then washed with a saturated aqueous solution of sodiumchloride and dried over anhydrous magnesium sulfate, after which thesolvent was removed by distillation under reduced pressure. Theresulting residue was purified by flash chromatography through 40 g ofsilica gel (Merck Art No. 9385), using a gradient elution method withmixtures of ethyl acetate and methanol ranging from 40:1 to 20:1 byvolume as the eluent, to give 3.63 g of the title compound as acolorless foam.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 1756, 1713, 1656,1529, 1443, 1405, 1347, 1251.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm:

0.11 (9H, singlet);

1.18 (3H, doublet, J=6.34 Hz);

1.23 (3H, doublet, J=6.84 Hz);

1.84-1.92 (1H, multiplet);

2.30-2.80 (8H, multiplet);

2.82-2.92 (1H, multiplet);

3.01 & 3.03 (together 1H, two doublets, J=1.71 & 5.13 Hz);

3.35-3.65 (4H, multiplet);

3.77 & 3.79 (together 1H, two doublets, J=1.71 & 5.86 Hz);

3.93-4.03 (1H, multiplet);

4.09-4.17 (2H, multiplet);

4.22-4.37 (2H, multiplet);

4.64-4.77 (1H, multiplet);

5.06 & 5.32 (together 1H, two doublets, J=13.67 & 13.67 Hz);

5.22 (1H, doublet, J=1.95 Hz);

5.26 (2H, singlet);

5.86 (1H, broad singlet);

7.44 & 7.50 (together 2H, two doublets, J=8.79 & 8.79 Hz);

7.55 (2H, doublet, J=8.79 Hz);

8.15-8.27 (4H, multiplet).

PREPARATION 16

(3S,4S)-3-[(1R)-1-(Trimethylsilyloxy)ethyl]-4-{2(S)-[4-(2-p-nitrobenzyloxycarbonyloxyethyl)piperazin-1-ylcarbonyl]-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-4(S)-yl]thiocarbonylethyl}-1-(4-nitrobenzyloxyoxalyl)azetidin-2-one##STR58##

1.39 g of triethylamine were added dropwise, whilst ice-cooling andunder a stream of nitrogen, to a solution of 3.94 g of(3S,4S)-3-[(1R)-1-(trimethylsilyloxy)ethyl]-4-{2(S)-[4-(2-p-nitrobenzyloxycarbonyloxyethyl)piperazin-1-ylcarbonyl]-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-4(S)-yl]thiocarbonylethyl}-azetidin-2-one(prepared as described in Preparation 15) in 30 ml of methylenechloride. A solution of 3.35 g of p-nitrobenzyloxyoxalyl chloride in 30ml of methylene chloride was then added to the mixture at a temperaturebelow 5° C. over a period of 15 minutes, and the resulting mixture wasstirred at the same temperature for 10 minutes. After this, 1.04 ml ofisopropanol were added dropwise, and the mixture was stirred for afurther 10 minutes. At the end of this time, the solvent was removed bydistillation under reduced pressure, and the resulting residue wasdiluted with 50 ml of ethyl acetate. The mixture was washed with coldwater and with a saturated aqueous solution of sodium chloride, in thatorder, and the organic layer was separated and dried over anhydrousmagnesium sulfate. The solvent was then removed by distillation underreduced pressure, to give 6.89 g of the title compound as an oil.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 1809, 1754, 1708,1524, 1348, 1253.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm:

0.03 (9H, singlet);

1.20 (3H, doublet, J=6.35 Hz);

1.28 (3H, doublet, J=6.83 Hz);

1.81-1.92 (1H, multiplet);

2.25-2.39 (1H, multiplet);

2.40-2.75 (6H, multiplet);

3.35-3.60 (6H, multiplet);

3.63-3.75 (1H, multiplet);

3.85-4.02 (1H, multiplet);

4.50-4.18 (1H, multiplet);

4.20-4.40 (4H, multiplet);

4.63 & 4.71 (together 1H, two triplets, J=7.81 & 7.81 Hz);

5.05 & 5.31 (together 1H, two doublets, J=13.18 & 13.18 Hz);

5.22 (1H, doublet, J=2.44 Hz);

5.25 (2H, singlet);

5.35 & 5.43 (together 2H, two doublets, J=12.90 & 12.90 Hz);

7.44 & 7.50 (together 2H, two doublets, J=8.79 & 8.79 Hz);

7.54 (2H, doublet, J=8.06 Hz);

7.57 (2H, doublet, J=8.06 Hz);

8.15-8.28 (6H, multiplet).

PREPARATION 17

4-Nitrobenzyl (1R,5S,6S)-2-{2(S)-[4-(2-4'-nitrobenzyloxycarbonyloxyethyl)-1-piperazinylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4(S)-ylthio}-6-[(R)-1-trimethylsilyloxy)ethyl]-1-methyl-1-carbapen-2-em-3-carboxylate##STR59##

A homogenous mixture of 6.89 g of(3S,4S)-3-[(1R)-1-(trimethylsilyloxy)ethyl]-4-{2(S)-[4-(2-p-nitrobenzyloxycarbonyloxyethyl)piperazin-1-ylcarbonyl]-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-4(S)-yl]-thiocarbonylethyl}-1-(4-nitrobenzyloxyoxalyl)azetidin-2-one(prepared as described in Preparation 16) and 11.2 ml of freshlydistilled triethyl phosphite was heated at 60° C. for 4 hours, whilststirring under an atmosphere of nitrogen. At the end of this time, anyexcess of triethyl phosphite was removed by distillation at atemperature below 30° C. and under reduced pressure. The residue waswashed three times, each time with 50 ml of hexane, and then again threetimes, each time with 50 ml of diisopropyl ether. The solvent was thenfinally removed by decantation, and the mixture was dried by evaporationunder reduced pressure, to give 6.68 g of an ylide as a brown oil.

5.18 g of this ylide were dissolved in 350 ml of freshly distilledmesitylene, and the solution was heated on an oil bath kept at 170°-175°C. for 7 hours whilst stirring and under an atmosphere of nitrogen. Atthe end of this time, the reaction mixture was cooled to roomtemperature and washed with ice-water and with a saturated aqueoussolution of sodium chloride, in that order. The resulting mixture wasdried over anhydrous magnesium sulfate and treated with active charcoal;the solvent was then removed by distillation under reduced pressure andat a temperature below 45° C. The residue was washed with diisopropylether and dried by evaporation under reduced pressure, to give 4.18 g ofthe title compound as a brown foam.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 1771, 1751, 1712,1657, 1607, 1522, 1442, 1404 1377, 1347, 1321.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm:

0.12 (9H, singlet);

1.26 (3H, doublet, J=6.35 Hz);

1.27 (3H, doublet, J=6.35 Hz);

1.81-2.00 (1H, multiplet);

2.32-2.78 (6H, multiplet);

3.20-3.27 (1H, multiplet);

3.27-3.75 (8H, multiplet);

4.00-4.37 (5H, multiplet);

4.63-4.78 (1H, multiplet);

5.07 & 5.30 (together 1H, two doublets, J=13.67 & 13.67 Hz);

5.22 (1H, singlet);

5.26 (2H, singlet);

5.25 & 5.47 (together 2H, two doublets, J=14.15 & 14.15 Hz);

7.44 & 7.51 (together 2H, two doublets, J=8.79 & 8.79 Hz);

7.55 (2H, doublet, J=8.79 Hz);

7.65 (2H, doublet, J=8.79 Hz);

8.18-8.25 (6H, multiplet).

PREPARATION 18

4-Nitrobenzyl (1R,5S,6S)-2-{2(S)-[2-4'-nitrobenzyloxycarbonyloxyethyl)-1-piperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4(S)-ylthio}-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate

A solution of 0.704 g of potassium fluoride in 11.6 ml of water and then1.61 ml of acetic acid were added, whilst ice-cooling, to a solution of4.18 g of 4-nitrobenzyl(1R,5S,6)-2-{2(S)-[4-(2-4'-nitrobenzyloxycarbonyloxyethyl)-1-piperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4(S)-ylthio}-6-[(R)-1-(trimethylsilyloxy)ethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (prepared as described inPreparation 17) in 39 ml of acetone, and the resulting mixture wasstirred for 45 minutes. At the end of this time, the reaction mixturewas freed from the solvent by distillation under reduced pressure. Theresulting residue was mixed with ethyl acetate, and the mixture waswashed with water and with a saturated aqueous solution of sodiumchloride, in that order. The mixture was dried, and the solvent wasremoved by distillation under reduced pressure. The residue was washedthree times with diethyl ether, to give 2.87 g of the title compound asa powder.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 1769, 1751, 1710,1653, 1607, 1521, 1443, 1347.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm:

1.27 & 1.28 (together 3H, two doublets, J=7.33 & 7.33 Hz);

1.37 (3H, doublet, J=6.35 Hz);

1.78-1.98 (1H, multiplet);

2.31-2.80 (7H, multiplet);

3.27 (1H, doublet of doublets, J=6.83 & 2.44 Hz);

3.31-3.76 (8H, multiplet);

4.01-4.33 (5H, multiplet);

4.68 & 4.74 (together 1H, two triplets, J=7.81 & 7.81 Hz);

5.04-5.52 (6H, multiplet);

7.44 & 7.51 (together 2H, two doublets, J=8.79 & 8.79 Hz);

7.55 & 7.65 (together 4H, two doublets, J=8.79 & 8.79 Hz);

8.17-8.25 (6H, multiplet).

The resulting compound can be converted to a known carbapenem derivativehaving excellent antibacterial activity by deprotecting the hydroxy- andcarboxy-protecting groups by conventional means.

PREPARATION 19

Z(O)-1-t-Butyldimethylsilyloxy-1-(2-diethylcarbamoylphenylthio)-1-propene and its E(O)-isomer

A solution of 729 mg (2.75 mmole) of S-2-diethylcarbamoylphenylthiopropionate (prepared as described in Preparation 30), 832 mg (5.52mmole) of t-butyldimethylsilyl chloride and 621 mg (3.47 mmole) ofhexamethylphosphoric triamide in 6 ml of tetrahydrofuran was cooled to-78° C., and 3.0 ml (3.0 mmole) of a 1.0M solution of lithiumbis(trimethylsilyl)amide in tetrahydrofuran was added dropwise to themixture over a period of 7 minutes. The resulting mixture was thenstirred at the same temperature for 10 minutes, after which the reactionwas terminated by adding 2 ml of a saturated aqueous solution of sodiumhydrogencarbonate. The reaction mixture was then mixed with hexane andwashed with water to remove tetrahydrofuran and hexamethylphosphorictriamide. The solvent was then removed by distillation under reducedpressure, and the resulting residue was purified by columnchromatography through 20 g of alumina, using a 1:1 by volume mixture ofmethylene chloride and hexane as the eluent, to give 922 mg (yield 88%)of the title compound as a colorless oil. By analysis of the nuclearmagnetic resonance spectrum (270 MHz), the product was shown to be amixture of the Z(O)- and E(O)-isomers in the ratio of 4 to 1.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm:

0.10 (1.2H, singlet);

0.11 (4.8H, singlet);

0.80 (7.2H, singlet);

0.89 (1.8H, singlet);

1.07 (3H, triplet, J=7 Hz);

1.27 (3H, triplet, J=7 Hz);

1.70 (0.8H, doublet, J=7 Hz);

1.78 (0.2H, doublet, J=7 Hz);

3.16 (1.6H, quartet, J=7 Hz);

3.18 (0.4H, quartet, J=7 Hz);

3.46-3.65 (2H, broad);

5.35 (1H, quartet, J=7 Hz);

7.11-7.20 (2H, multiplet);

7.22-7.32 (1H, multiplet);

7.37-7.45 (1H, multiplet).

PREPARATIONS 20 TO 29

Following a similar procedure to that described in Preparation 19, thefollowing compounds were also prepared.

PREPARATION 20

Z(O)-1-t-Butyldimethylsilyloxy-1-(2-dimethylcarbamoylphenylthio)-1-propene and its E(O)-isomer

The yield of the Z(O)-isomer was 85%, and the ratio of the yields ofZ(O)-isomer to E(O)-isomer was 4:1.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm:

0.10 (1.2H, singlet);

0.11 (4.8H, singlet);

0.79 (1.8H, singlet);

0.89 (7.2H, singlet);

1.70 (2.4H, doublet, J=7 Hz);

1.78 (0.6H, doublet, J=7 Hz);

2.88 (3H, singlet);

3.12 (3H, singlet);

5.33 (0.2H, quartet, J=7 Hz);

5.35 (0.8H, quartet, J=7 Hz);

7.15-7.20 (2H, multiplet);

7.24-7.33 (1H, multiplet);

7.40-7.47 (1H, multiplet).

PREPARATION 21

Z(O)-1-t-Butyldimethylsilyloxy-1-(2-dipropylcarbamoylphenylthio)-1-propeneand its E(O)-isomer

The yield of the Z(O)-isomer was 88%, and the ratio of the yields ofZ(O)-isomer to E(O)-isomer was 2:1.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm:

0.10 (2H, singlet);

0.11 (4H, singlet);

0.73 (3H, triplet, J=7 Hz);

0.81 (3H, singlet);

0.89 (6H, singlet);

1.00 (3H, triplet, J=7 Hz);

1.43-1.60 (2H, multiplet);

1.62-1.80 (2H, multiplet);

1.70 (2H, doublet, J=7 Hz);

1.77 (1H, doublet, J=7 Hz);

3.05 (1.3H, triplet, J=7 Hz);

3.08 (0.7H, triplet, J=7 Hz);

3.46-3.60 (2H, broad singlet);

5.35 (0.67H, quartet, J=7 Hz);

5.37 (0.33H, quartet, J=7 Hz);

7.10-7.19 (2H, multiplet);

7.22-7.31 (1H, multiplet);

7.36-7.31 (1H, multiplet);

7.36-7.44 (1H, multiplet).

PREPARATION 22

Z(O)-1-t-Butyldimethylsilyloxy-1-(2-diisobutylcarbamoylphenylthio)-1-propene and its E(O)-isomer

The yield of the Z(O)-isomer was 58%, and the ratio of the yields ofZ(O)-isomer to E(O)-isomer was 7:1.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm:

0.11 (6H, singlet);

0.75 (5.3H, doublet, J=7 Hz);

0.77 (0.7H, doublet, J=7 Hz);

0.82 (1.1H, singlet);

0.90 (7.9H, singlet);

1.03 (6H, doublet, J=7 Hz);

1.71 (2.6H, doublet, J=7 Hz);

1.76 (0.4H, doublet, J=7 Hz);

1.80-1.95 (1H, multiplet);

2.07-2.25 (1H, multiplet);

2.99 (1.75H, doublet, J=8 Hz);

3.02 (0.25H, doublet, J=8 Hz);

3.10-3.70 (2H, broad singlet);

5.36 (0.88H, quartet, J=7 Hz);

5.42 (0.12H, quartet, J=7 Hz);

7.09-7.22 (2H, multiplet);

7.23-7.30 (1H, multiplet);

7.34-7.42 (1H, multiplet).

PREPARATION 23

Z(O)-1-t-Butyldimethylsilyloxy-1-(2-N-methyl-N-phenylcarbamoylphenylthio)-1-propene and its E(O)-isomer

The yield of the Z(O)-isomer was 87%, and the ratio of the yields ofZ(O)-isomer to E(O)-isomer was 9:1.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm:

0.10 (0.6H, singlet);

0.15 (5.4H, singlet);

0.84 (0.9H, singlet);

0.92 (8.1H, singlet);

1.69 (2.7H, doublet, J=7 Hz);

1.79 (0.3H, doublet, J=7 Hz);

3.35-3.55 (3H, broad singlet);

5.34 (0.9H, quartet, J=7 Hz);

5.39 (0.1H, quartet, J=7 Hz);

6.85-7.27 (8H, broad);

7.31-7.38 (1H, broad).

PREPARATION 24

Z(O)-1-t-Butyldimethylsilyloxy-1-[2-(1-piperidyl)-carbonylphenylthio]-1-propeneand its E(O)-isomer

The yield of the Z(O)-isomer was 94%, and the ratio of the yields of theZ(O)-isomer to E(O)-isomer was 3:1.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm:

0.10 (1.5H, singlet);

0.11 (4.5H, singlet);

0.80 (2.3H, singlet);

0.89 (6.7H, singlet);

1.40-1.73 (6H, broad);

1.69 (2.25H, doublet, J=7 Hz);

1.77 (0.75H, doublet, J=7 Hz);

3.15-3.28 (2H, broad);

3.55-3.95 (2H, broad);

5.34 (0.25H, quartet, J=7 Hz);

5.35 (0.75H, quartet, J=7 Hz);

7.10-7.19 (2H, multiplet);

7.22-7.32 (1H, multiplet);

7.38-7.46 (1H, multiplet).

PREPARATION 26

Z(O)-1-t-Butyldimethylsilyloxy-1-[2-morpholinocarbonylphenylthio]-1-propeneand its E(O)-isomer

The yield of the Z(O)-isomer was 99%, and the ratio of the yields of theZ(O)-isomer to E(O)-isomer was 5:1.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm:

0.10 (1H, singlet);

0.11 (5H, singlet);

0.79 (1.5H, singlet);

0.89 (7.5H, singlet);

1.70 (2.5H, doublet, J=7 Hz);

1.78 (0.5H, doublet, J=7 Hz);

3.18-3.40 (2H, broad);

3.52-3.85 (2H, broad singlet);

3.65-3.90 (4H, broad singlet);

5.34 (0.17H, quartet, J=7 Hz);

5.35 (0.83H, quartet, J=7 Hz);

7.13-7.21 (2H, multiplet);

7.25-7.36 (1H, multiplet);

7.40-7.47 (1H, multiplet).

PREPARATION 27

Z(O)-1-t-Butyldimethylsilyloxy-1-[2-(1-azepinyl)-carbonylphenylthio]-1-propeneand its E(O)-isomer

The yield of the Z(O)-isomer was 86%, and the ratio of the yields of theZ(O)-isomer to E(O)-isomer was 3:1.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm:

0.10 (1.5H, singlet);

0.12 (4.5H, singlet);

0.79 (2.3H, singlet);

0.90 (6.7H, singlet);

1.53-1.72 (6H, broad);

1.69 (2.25H, doublet, J=7 Hz);

1.78 (0.75H, doublet, J=7 Hz);

1.75-1.90 (2H, broad);

3.19-3.35 (2H, broad);

3.35-3.80 (2H, broad);

5.33 (0.25H, quartet, J=7 Hz);

5.34 (0.75H, quartet, J=7 Hz);

7.10-7.19 (2H, multiplet);

7.21-7.33 (1H, multiplet);

7.38-7.46 (1H, multiplet).

PREPARATION 28

Z(O)-1-t-Butyldimethylsilyloxy-1-(2-diethylcarbamoyl-6-methylphenylthio)-1-propene and its E(O)-isomer

The yield of the Z(O)-isomer was 76%, and the ratio of the yields of theZ(O)-isomer to E(O)-isomer was 11:1.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm:

0.21 (3H, singlet);

0.23 (3H, singlet);

0.96 (9H, singlet);

1.03 (3H, triplet, J=7 Hz);

1.27 (3H, triplet, J=7 Hz);

1.49 (3H, doublet, J=7 Hz);

2.51 (3H, singlet);

3.08 (1H, doublet of quartets, J=14 & 7 Hz);

3.11 (1H, doublet of quartets, J=14 & 7 Hz);

3.43 (1H, doublet of quartets, J=14 & 7 Hz);

4.12 (1H, quartet, J=7 Hz);

7.08-7.13 (1H, multiplet);

7.25-7.32 (2H, multiplet).

PREPARATION 29

Z(O)-1-t-Butyldimethylsilyloxy-1-[2-diethyl(thiocarbamoyl)-6-methylphenylthio]-1-propene and its E(O)-isomer

The yield of the Z(O)-isomer was 100%, and the ratio of the yields ofthe Z(O)-isomer to E(O)-isomer was 20:1.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm:

0.12 (3H, singlet);

0.14 (3H, singlet);

0.80 (9/21H, singlet);

0.90 (180/21H, singlet);

1.11 (3H, triplet, J=7 Hz);

1.40 (3H, triplet, J=7 Hz);

1.70 (60/21H, doublet, J=7 Hz);

1.78 (3/21H, doublet, J=7 Hz);

3.29 (1H, doublet of quartets, J=14 & 7 Hz);

3.44 (1H, doublet of quartets, J=14 & 7 Hz);

3.67 (1H, quartet, J=7 & 14 Hz);

4.57 (1H, doublet of quartets, J=7 & 14 Hz);

5.37 (1H, quartet, J=7 Hz);

7.10-7.25 (3H, multiplet);

7.31-7.40 (1H, multiplet).

PREPARATION 30

S-2-Diethylcarbamoylphenyl thiopropionate

Method A

A solution of 34.84 g (0.476 mole) of diethylamine and 70.0 ml (0.502mole) of triethylamine in 50 ml of methylene chloride was addeddropwise, over a period of 1 hour, to an ice-cooled suspension of 71.62g of (0.209 mole) of 2,2'-dithiobenzoyl chloride in 300 ml of methylenechloride, and the resulting mixture was stirred at the same temperaturefor a further 30 minutes. At the end of this time, the solvent wasremoved by distillation under reduced pressure, and the resultingresidue was diluted with ethyl acetate. The resulting organic solutionwas washed with water and with a saturated aqueous solution of sodiumchloride, in that order. The solvent was again distilled off to give anamide compound. About 4 g of this amide compound was mixed with 14.36 g(0.220 mole) of zinc powder and 80.0 (0.624 mole) of propionicanhydride, and the mixture was heated at 100° C. for 5 minutes. In thecourse of this reaction, the zinc in the reaction mixture was activated.The remainder of the amide compound was dissolved in 100 ml of benzene,and the resulting solution was then added dropwise to the reactionmixture at the same temperature over a period of 20 minutes. Theresulting mixture was then heated under reflux for 90 minutes, afterwhich it was cooled. The crystals which separated were collected byfiltration and washed with ethyl acetate. The filtrate and the washingswere combined, and the resulting mixture was washed with water; thesolvent was then removed by distillation under reduced pressure. Theresidue was then subjected to fractional distillation under reducedpressure, to give 106.97 g of the title compound, boiling at 167°-170°C./0.95-1.1 mmHg (12.7-14.7 Pa), representing a total yield of 96% overthe two steps.

Infrared Absorption Spectrum (CHCl₃), ν_(max) cm⁻¹ : 1710, 1635, 1292,932.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm:

1.02 (3H, triplet, J=7 Hz);

1.20 (3H, triplet, J=7 Hz);

1.23 (3H, triplet, J=7 Hz);

2.66 (2H, quartet, J=7 Hz);

2.90-3.20 (2H, broad);

3.10-4.00 (2H, broad);

7.29-7.36 (1H, multiplet);

7.40-7.52 (1H, multiplet).

Mass spectrum (m/z): 266 (M⁺ +1), (M⁺, C₁₄ H₁₉ NO₂ S).

Method B

30B(i) N,N-diethyl-2-benzoylthiobenzamide

2.85 (20.3 mmole) of benzoyl chloride were added dropwise, whilstice-cooling, to a solution of 3.13 g (20.3 mmole) of thiosalicylic acidand 2.46 g )24.4 mmole) of triethylamine in 60 ml of methylene chloride,and the resulting mixture was stirred at room temperature for 1 hour. Atthe end of this time, the reaction mixture was washed twice with 0.2Naqueous hydrochloric acid and once with a saturated aqueous solution ofsodium chloride, and the solvent was removed by distillation underreduced pressure, to give 5.24 g of benzoylthiobenzoic acid as crudecrystals in a quantitative yield. The whole of this product wasdissolved in 100 ml of methylene chloride, and 5.45 g (21.3 mmole) of2-chloro-1-methylpyridinium iodide, 1.78 g (24.4 mmole) of diethylamineand 4.51 g (44.7 mmole) of triethylamine were added, in that order, tothe resulting solution, whilst ice-cooling. The resulting mixture wasthen stirred at room temperature for 20 hours, after which the solventwas removed by distillation under reduced pressure. The residue waspartitioned between ethyl acetate and dilute aqueous hydrochloric acid,and the organic layer was washed with water. The solvent was removed bydistillation under reduced pressure, and the residue was purified bycolumn chromatography through 120 g of silica gel, using a gradientelution method with mixtures of hexane and acetone ranging from 4:1 to3:1 by volume as the eluent, to give 4.86 g of the title compound as anoil in a 76% yield.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 60 MHz), δ ppm:

0.99 (3H, triplet, J=7 Hz);

1.02 (3H, triplet, J=7 Hz);

3.09 (2H, quartet, J=7 Hz);

3.0-3.9 (2H, broad);

7.2-7.7 (7.5H, multiplet);

7.9-8.2 (1.5H, multiplet).

30B(ii) S-2-Diethylcarbamoylphenyl thiopropionate

0.84 g (15.5 mmole) of sodium methoxide was added, whilst ice-cooling,to a solution of 4.86 g (15.5 mmole) ofN,N-diethyl-2-benzoylthiobenzamide [prepared as described in step (i)above] in 60 ml of methanol, and the resulting mixture was stirred for20 minutes. At the end of this time, the reaction mixture wasneutralized by adding about 15 drops of concentrated aqueoushydrochloric acid. Ethanol and was then added, and the solvent wasremoved by distillation under reduced pressure. In order to eliminatemoisture, the residue was mixed with 20 ml of ethanol and 30 ml ofbenzene and the solvent was removed by distillation under reducedpressure. The resulting residue, containingN,N-diethyl-2-mercaptobenzamide, was suspended in 60 ml of methylenechloride, and 4.30 g (46.5 mmole) of propionyl chloride wand 6.26 g(62.0 mmole) of triethylamine were added, whilst ice-cooling. Thereaction mixture was then stirred for 2.5 hours, after which thereaction was terminated by adding water. The reaction mixture was thendiluted with methylene chloride and the organic layer was washed firstwith dilute aqueous hydrochloric acid and then with water. The solventwas removed by distillation under reduced pressure, and the resultingresidue was purified by column chromatography through 100 g of silicagel, to give 3.26 g (yield 79%) of the title compound. The productobtained by this method was identical with that prepared in Method A.

PREPARATIONS 31 TO 38

Following the procedure described in Preparation 30 (Method A or B), thefollowing compounds were prepared. In these Preparations, only theinfrared carbonyl group absorption is reported.

PREPARATION 31

S-2-Dimethylcarbamoylphenyl thiopropionate

The title compound was obtained in a total yield of 78% for the twosteps.

Infrared Absorption Spectrum (liquid), ν_(max) cm⁻¹ : 1709, 1639.

PREPARATION 32

S-2-Dipropylcarbamoylphenyl thiopropionate

The title compound was obtained in a total yield of 93% for the twosteps.

Infrared Absorption Spectrum (liquid), ν_(max) cm⁻¹ : 1705, 1632.

PREPARATION 33

S-2-Diisobutylcarbamoylphenyl thiopropionate

The title compound was obtained in a total yield of 99% for the twosteps.

Infrared Absorption Spectrum (liquid), ν_(max) cm⁻¹ : 1712, 1635.

PREPARATION 34

S-2-(N-Methyl-N-phenylcarbamoyl)phenyl thiopropionate

The title compound was obtained in a total yield of 96% for the twosteps.

Infrared Absorption Spectrum (liquid), ν_(max) cm⁻¹ : 1705, 1645.

PREPARATION 35

S-2-(1-Pyrrolidinylcarbonyl)phenyl thiopropionate

The title compound was obtained in a total yield of 74% for the twosteps.

Infrared Absorption Spectrum (liquid), ν_(max) cm⁻¹ : 1702, 1630.

PREPARATION 36

S-2-(1-Piperidylcarbonyl)phenyl thiopropionate

The title compound was obtained in a total yield of 98% for the twosteps.

Infrared Absorption Spectrum (liquid), ν_(max) cm⁻¹ : 1702, 1630.

PREPARATION 37

S-2-Morpholinocarbonylphenyl thiopropionate

The title compound was obtained in a total yield of 89% for the twosteps.

Infrared Absorption Spectrum (liquid), ν_(max) cm⁻¹ : 1702, 1635.

PREPARATION 38

S-2-(1-Azepinylcarbonyl)phenyl thiopropionate

The title compound was obtained in a total yield of 93% for the twosteps.

Infrared Absorption Spectrum (liquid), ν_(max) cm⁻¹ : 1705, 1630.

PREPARATION 39

(3S,4S)-3-[(1R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-{2(S)-[4-(2-p-nitrobenzyloxycarbonyloxyethyl)-piperazin-1-ylcarbonyl]-1-(p-nitrobenzyloxycarbonyl)-pyrrolidin-4(S)-yl]-thiocarbonylethyl}azetidin-2-one

A solution of 99 mg (0.20 mmole) of S-2-diethylcarbamoylphenyl2(R)-{(3S,4S)-3-[1(R)-(t-butyldimethylsilyloxy)ethyl]-2-oxo-4-azetidinyl}thiopropionate(prepared as described in Example 6), 135 mg (0.22 mmole) of(2S,4S)-2-{4-[2-(4-nitrobenzyloxycarbonyl)oxyethyl]-1-piperazinylcarbonyl}-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine and 30 mg (0.30 mmole) of triethylamine in 2 ml of methylenechloride was stirred at room temperature for 17 hours. At the end ofthis time, the solvent was removed by distillation under reducedpressure, and the residue was dissolved in ethyl acetate. The resultingsolution was washed with a 2N aqueous solution of sodium hydroxide, withwater and with a saturated aqueous solution of sodium chloride, in thatorder. The solvent was then removed by distillation under reducedpressure, and the residue was purified by column chromatography through25 g of silica gel, using a 3:2 by volume mixture of acetone and hexaneas the eluent, to give 182 mg of the title compound as a foam in aquantitative yield.

PREPARATION 40

(3S,4S)-3-[(1R)-1-Hydroxyethyl]-4-{2(S)-[4-(2-p-nitrobenzyloxycarbonyloxyethyl)-piperazin-1-ylcarbonyl]-1-(p-nitrobenzyloxycarbonyl)pyrrolidin-4(S)-yl]-thiocarbonylethyl}azetidin-2-one

24 ml of 3N aqueous hydrochloric acid were added dropwise, whilstice-cooling and stirring, to a solution of 8.1 g of(3S,4S)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{1(R)-{2(S)-[4-(2-4'-nitrobenzyloxycarbonyloxyethyl)piperazin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4(S)-ylthiocarbonyl}ethyl}-azetidin-2-one (prepared asdescribed in Preparation 39) in 80 ml of methanol, and the mixture wasstirred at the same temperature for 30 minutes and then allowed to standovernight in a refrigerator. At the end of this time, the reactionmixture was ice-cooled and its pH was adjusted to a value of 5 to 6 bythe addition of sodium hydrogencarbonate. The mixture was thenconcentrated by evaporation under reduced pressure, and the resultingresidue was mixed with a small amount of water and extracted with ethylacetate. The aqueous layer was saturated with sodium chloride andextracted with ethyl acetate. The extracts were combined and then freedfrom the solvent by distillation under reduced pressure. The residue waspurified by column chromatography through 150 g of silica gel, using agradient elution method with mixtures of ethyl acetate and methanolranging from 20:1 to 10:1 by volume as the eluent, to give 5.9 g of thetitle compound as a colorless foam.

Infrared Absorption Spectrum (CHCl₃), ν_(max) cm⁻¹ : 1752, 1710, 1650,1607, 1522, 1443, 1404, 1347, 1263.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm:

1.27 (3H, doublet, J=6.83 Hz);

1.28 (3H, doublet, J=6.35 Hz);

1.82-1.99 (1H, multiplet);

2.10-2.18 (1H, multiplet);

2.40-2.95 (7H, multiplet);

3.03 (1H, doublet of doublets, J=1.95 & 6.35 Hz);

3.37-3.80 (5H, multiplet);

3.78 (1H, doublet of doublets, J=1.95 & 6.84 Hz);

3.95-4.48 (6H, multiplet);

4.68 & 4.73 (together 1H, two triplets, J=8.06 & 7.33 Hz);

5.06 & 6.32 (together 1H, two doublets, J=13.43 & 13.43 Hz);

5.21 (1H, singlet);

5.26 (2H, singlet);

5.99 (1H, broad);

7.45 & 7.50 (together 2H, two doublets, J=8.30 & 8.79 Hz);

7.56 (2H, doublet, J=8.79 Hz);

8.18-8.26 (4H, multiplet).

PREPARATION 41

S-2-diethylaminocarbonyl-6-methylphenyl thiopropionate

Following a procedure similar to that described in Preparation 30(Method A), the title compound was obtained in a yield of 38%.

Infrared Absorption Spectrum (Kbr), ν_(max) cm⁻¹ : 1703, 1635.

PREPARATION 42

S-2-diethylaminothiocarbonylphenyl thiopropionate

216 mg (0.534 mmole) of Lawesson's reagent were added to a solution of276 mg (1.04 mmole) of S-2-diethylcarbamoylphenyl thiopropionate(prepared as described in Preparation 30) in 5 ml of toluene, and theresulting mixture was stirred at 100° C. for 20 minutes. It was thencooled, and the resulting mixture was purified by column chromatographythrough 25 g of silica gel, using a gradient solution method, withmixtures of methylene chloride and hexane ranging from 3:0 to 3:1 byvolume as the eluent, to give 386 mg of the title compound, melting at67.5°-68.5° C.

Infrared Absorption Spectrum (Nujol), ν_(max) cm⁻¹ : 1712, 1505, 1308,1242, 928.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm:

1.08 (3H, triplet, J=7 Hz),

1.20 (3H, triplet, J=7 Hz),

1.37 (3H, triplet, J=7 Hz),

2.66 (2H, quartet, J=7 Hz),

3.19 (1H, doublet of quartets, J=14 & 7 Hz),

3.38 (1H, doublet of doublets, J=14 & 7 Hz),

3.70 (1H, doublet of quartets, J=14 & 7 Hz),

4.53 (1H, doublet of doublets, J=14 & 7 Hz),

7.25 (1H, doublet of quartets, J=7 & 3 Hz),

7.31-7.47 (3H, multiplet).

Mass spectrum (m/z): 281 (M⁺, C₁₄ H₁₉ NOS₂).

PREPARATION 43

2-Diethylcarbamoylphenyl propionate

2.0 ml (23 mmole) of oxalyl chloride and 0.050 ml ofN,N-dimethylformamide were added, whilst ice-cooling, to a solution of2.40 g (12.4 mmole) of 2-propionyloxybenzoic acid in 24 ml of methylenechloride, and the resulting mixture was stirred for 1 hour. At the endof this time, the solvent and excess oxalyl chloride were removed bydistillation under reduced pressure, and 20 ml of methylene chloridewere added to the residue, 1.36 g (13.5 mmole) of triethylamine and 986mg 13.5 mmole) of diethylamine were then added, whilst ice-cooling, tothe resulting solution, and the mixture was stirred for 1 hour. Themixture was then diluted with ethyl acetate, and the organic layer waswashed with water. The solvent was removed by distillation under reducedpressure, and the residue was purified by column chromatography through25 g of silica gel, using a gradient elution method, with mixtures ofmethylene chloride and ethyl acetate ranging from 10:1 to 7:1 by volumeas the eluent, to give 3.0 g (yield 97%) of 2-diethylamioncarbonylphenylpropionate as an oil.

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻¹ : 1765, 1638,1430, 1293, 1142.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 60 MHz), δ ppm:

1.06 (3H, triplet, J=7 Hz),

1.20 (6H, triplet, J=7 Hz),

2.52 (2H, quartet, J=7 Hz),

3.15 (2H, quartet, J=7 Hz),

3.49 (2H, quartet, J=7 Hz),

7.0-7.6 (4, multiplet).

Mass spectrum (m/z): 249 (M⁺, C₁₄ H₁₉ NO₃).

EXAMPLE 18

4-Nitrobenzyl(1R,5S,6S)-2-[(3S,5S)-5-dimethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-3-pyrrolidinylthio]-1-methyl-6-[1(R)-trimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate##STR60##

2 ml of a tetrahydrofuran solution containing 68 mg (0.19 mmol) of(2S,4)-2-dimethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-4-mercaptopyrrolidine were cooled in tetrahydrofuran solution ofbromomagnesium N-isopropyl-N-cyclohexylamide were added dropwise over aperiod of 2 minutes. The mixture was stirred for a further 10 minutes atthis temperature, and then 1 ml of a tetrahydrofuran solution containing100 mg of 4-nitrobenzyl(1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-trimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate(prepared as described in Example 38) was added. The mixture was stirredfor a further 15 minutes at this temperature, after which ice water wasadded. The reaction mixture was then diluted with ethyl acetate, washedwith an aqueous solution of ammonium chloride then with a saturatedaqueous solution of sodium chloride. The solvent was then removed bydistillation under reduced pressure, and the resulting residue waspurified by column chromatography through 10 g of silica gel, elutedwith ethyl acetate, to give 94 mg (yield 78%) of the title compound as afoam-like solid.

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻¹ : 1773, 1711,1655, 1522, 1345, 1142, 845.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

0.13 (4.5H, singlet);

0.14 (4.5H, singlet);

1.25-1.29 (6H, multiplet);

1.89-2.00 (1H, multiplet);

2.67-2.80 (1H, multiplet);

2.94 (1.5H, singlet);

2.98 (1.5H, singlet);

3.00 (1.5H, singlet);

3.11 (1.5H, singlet);

3.22-3.27 (1H, multiplet);

3.30-3.40 (1H, multiplet);

3.46-3.57 (1H, multiplet);

3.60-3.76 (1H, multiplet);

4.02-4.30 (3, multiplet);

4.72 (0.5H, triplet, J=8 Hz);

4.76 (0.5H, triplet, J=8 Hz);

5.07 (0.5H, doublet, J=14 Hz);

5.22 (1H, singlet);

5.25 (1H, doublet, J=14 Hz);

5.30 (0.5H, doublet, J=14 Hz);

5.46 (1H, doublet, J=14 Hz);

7.44 (1H, doublet, J=9 Hz);

7.52 (1H, doublet, J=9 Hz);

7.65 (2H, doublet, J=9 Hz);

8.20 (1H, doublet, J=9 Hz);

8.21 (3H, doublet, J=9 Hz).

Mass spectrum (m/z): 754 [M⁺ (C₃₅ H₄₃ N₅ O₁₁ Ssi)-CH₃ ].

EXAMPLE 19

4-Nitrobenzyl(1R,5S,6S)-2-[(2S,4S)-2-dimethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-4-pyrrolidinylthio]-1-methyl-6-[1(R)-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate##STR61## (a) Following a procedure similar to that described in Example18, but using 4-nitrobenzyl(1R,5S,6S)-2-dimethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate(prepared as described in Example 39), the title compound was obtainedas a foam-like solid in a yield of 86%.

(b) Following a procedure similar to that described in Example 18, butusing 4-nitrobenzyl(1R,5S,6S)-2-[2-(2H-1,3,4,5,6,7-hexahydro-1-azepinyl)carbonylphenylsulfinyl]-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate(prepared as described in Example 41), the title compound was obtainedas a foam-like solid in a yield of 83%.

(c) 25 μl (0.144 mmol) of diisopropylethylamine were added to 2 ml of atetrahydrofuran suspension containing 50 mg (0.071 mmol) of4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfonyl)-1-methyl-6-[1(R)-t-butyldimethyl-silyloxyethyl]-1-carbapen-2-em-3-carboxylate(prepared as described in Example 42), 30 mg (0.086 mmol) of(2S,4S)-dimethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-4-mercaptopyrrolidineand 76 mg (0.294 mmol) of a magnesium bromide-diethyl ether complex. Theresulting suspension was then stirred for 94 hours. At the end of thistime, the reaction solution was diluted with ethyl acetate, washed withwater and then with a saturated aqueous solution of sodium chloride. Thesolvent was then removed by distillation under reduced pressure, and theresulting residue was purified by column chromatography through silicagel, using a 1:1 by volume mixture of methylene chloride and ethylacetate as the eluent, to obtain 40 mg (yield 69%) of the title compoundas a foam-like solid.

(d) Following a procedure similar to that described in Example 18, butusing 76 mg of 4-nitrobenzyl(1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfonyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate(prepared as described in Example 42) and 46 mg of(2S,4S)-dimethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-4-mercaptopyrrolidine,the title compound was obtained in a yield of 78%.

(e) Following a procedure similar to that described in Example 18, butusing 101 mg of 4-nitrobenzyl(1R,5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-methyl-2-[2-(4-nitrobenzyloxycarbonyl)aminoethylsulfinyl)-1-carbapen-2-em-3-carboxylate(prepared as described in Preparation 48) and 61 mg of(2S,4S)-dimethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-4-mercaptopyrrolidine,the title compound was obtained in a yield of 83%.

(f) Following a procedure similar to that described in Example 18, 100mg of 4-nitrobenzyl (1R,5S,6S,)-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-methyl-2-ethylsulfinyl-1-methyl-1-carbapen-2-em-3-carboxylate(prepared as described in Preparation 49) was allowed to react with 79mg of(2S,4S)-dimethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-4-mercaptopyrrolidine,and the product was purified by silica gel column chromatography, usingethyl acetate as the eluent, to give a fraction containing the titlecompound in a yield of 87%. This fraction, which contained impuritieswhich could not be separated by silica gel column chromatography, showeda purity of 83.5% by as determined the area ratio according to liquidchromatography.

(g) 75 μl of a hexane solution containing 1.6M of butyllithium was addedto 1 ml of an ice-cooled toluene solution containing 18 μl (0.13 mmol)of diisopropylamine, and the mixture was stirred for 10 minutes. At theend of this time, 125 μl (0.12 mmol) of a hexane solution containing0.97M of diethylaluminium chloride was added and the mixture was stirredfor a further 20 minutes at this temperature. The diethylaluminiumdiisopropylamide solution thus obtained was added to 2 ml of anice-cooled tetrahydrofuran solution containing 43 mg (0.12 mmol) of2S,4S)-dimethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-4-mercaptopyrrolidine,and stirred for 15 minutes at this temperature. At the end of this time,1 of a tetrahydrofuran solution containing 68 mg (0.10 mmol) of4-nitrobenzyl(1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate(prepared as described in Example 39) was added to the reaction mixture,and the mixture was stirred for 105 minutes. A saturated aqueoussolution of ammonium chloride and then ethyl acetate were added, and theprecipitate which formed was removed. The organic layer was separated,and washed with water and then with a saturated aqueous solution ofsodium chloride. The solvent was then removed by distillation underreduced pressure. The resulting residue was purified by columnchromatography through 10 g of silica gel, using a 1:3 by volume mixtureof benzene and ethyl acetate as the eluent, to obtain 60 mg of afraction containing the title compound in a yield of 74%. This fractionshowed a plurality of 56% as determined by the area ratio according toliquid chromatography.

The properties of the title compound obtained in (a) to (g) above areshown below.

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻ : 1775, 1713,1657, 1522, 1345, 1142, 837.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

0.07-0.09 (6H, multiplet);

0.85 (4.5H, singlet);

0.87 (4.5H, singlet);

1.23-1.29 (6H, multiplet);

1.88-2.00 (1H, multiplet);

2.67-2.81 (1H, multiplet);

2.94 (1.5H, singlet);

2.98 (1.5H, singlet);

2.99 (1.5H, singlet);

3.11 (1.5H, singlet);

3.23-3.41 (2H, multiplet);

3.46-3.57 (1H, multiplet);

3.61-3.78 (1H, multiplet);

4.03-4.32 (3H, multiplet);

4.73 (0.5H, triplet, J=8 Hz);

4.77 (0.5H, triplet, J=8 Hz);

5.07 (0.5H, doublet, J=13 Hz);

5.22 (1H, singlet);

5.25 (1H, doublet, J=13 Hz);

5.30 (0.5H, doublet, J=13 Hz);

5.45 (1H, doublet, J=13 Hz);

7.45 (1H, doublet, J=9 Hz);

7.52 (1H, doublet, J=9 Hz);

7.65 (2H, doublet, J=9 Hz);

8.20 (1H, doublet, J=9 Hz);

8.21 (3H, doublet, J=9 Hz).

Mass spectrum (m/z): 754 (M⁺ (C₃₈ H₄₉ N₅ O₁₁ Ssi)-C₄ H₉)

EXAMPLE 20

4-Nitrobenzyl (1R,5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-methyl-2-{(2S,4S)-2-[4-{2-(4-nitrobenzyloxycarbonyloxy)ethyl}piperazin-1-yl-carbonyl]-1-[(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]}-1-carbapen-2-em-3-carboxylate ##STR62## (a)Following a procedure similar to that described in Example 18, but using4-nitrobenzyl(1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-3-carboxylate(prepared as described in Example 39) and(2S,4S)-4-mercapto-2-{4-[2-(4-nitrobenzyloxycarbonyloxy)ethyl]-piperazin-1-ylcarbonyl}-1-(4-nitrobenzyloxycarbonyl)-pyrrolidineas starting materials, in relative proportions similar to those used inthat Example, the title compound was obtained in a yield of 86%.Recrystallization of this product from toluene afforded it in the formof crystals, melting at 134°-136° C.

b) Following a procedure similar to that described in of Example 19(c),but using 4-nitrobenzyl(1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfonyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-3-carboxylate(prepared as described in Example 42) and(2S,4S)-4-mercapto-2-{4-[2-(4-nitrobenzyloxycarbonyloxy)ethyl]-piperazin-1-ylcarbonyl}-1-(4-nitrobenzyloxycarbonyl)-pyrrolidineas starting materials, in relative proportions similar to those used inthat Example, the title compound was obtained in a yield of 60%.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 1773, 1750, 1709,1653, 1522, 1345, 1260, 1146, 837.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

0.06-0.09 (6H, multiplet);

0.85 (4.5H, singlet);

0.86 (4.5H, singlet);

1.22-1.29 (6H, multiplet);

1.84-1.99 (1H, multiplet);

2.38-2.81 (7H, multiplet);

3.23-3.77 (8H, multiplet);

4.04-4.32 (5H, multiplet);

4.73 (1H, doublet of triplets, J=14 & 8 Hz);

5.07 (0.5H, doublet, J=14 Hz);

5.22 (1H, singlet);

5.26 (2H, singlet);

5.25 (1H, doublet, J=14 Hz);

5.30 (0.5H, doublet, J=14 Hz);

5.45 (1H, doublet, J=14 Hz);

7.44 (1H, doublet, J=9 Hz);

7.52 (1H, doublet, J=9 Hz);

7.56 (2H, doublet, J=9 Hz);

7.65 (2H, doublet, J=9 Hz);

8.17-8.26 (6H, multiplet).

EXAMPLE 21

4-Nitrobenzyl (1R,5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-methyl-2-{1(S)-[N-(4-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidin-3-ylthio}-1-carbapen-2-em-3-carboxylate##STR63## a) Following a procedure similar to that described in Example18, but using 4-nitrobenzyl(1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate(prepared as described in Example 39) and(S)-3-mercapto-1-[N-(4-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidine asstarting materials, in relative proportions similar to those used inthat Example, the title compound was obtained in a yield of 79%.Recrystallization from a mixture of diisopropyl ether and ethyl acetateafforded it in the form of crystals, melting at 171°-172.5° C.

(b) 4 ml of a tetrahydrofuran suspension containing 101 mg (1.148 mmol)of 4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate(prepared as described in Example 39), 106 mg (0.328 mmole) of(S)-3-mercapto-1-[N-(4-nitrobenzyloxycarbonyl) acetimidoyl]pyrrolidine,and 155 mg (0.600 mmol) of a magnesium bromide-diethyl ether complex wasstirred for 6 hours. At the end of this time, the reaction mixture wasdiluted with ethyl acetate, and washed with water and then with asaturated aqueous solution of sodium chloride. The solvent was thenremoved by distillation under reduced pressure. The resulting residuewas purified by column chromatography through 5 g of silica gel. Thetitle compound containing a small amount of impurities was obtained byelution with a 1:1 by volume mixture of hexane and ethyl acetate. Thisimpure compound was purified by additional chromatography through 5 g ofsilica gel followed by elution with a 1:3 by volume mixture of ethylacetate and methylene chloride, to afford 74 mg (yield 64%) of the titlecompound.

(c) Following a procedure similar to that described in Example 19(c),but using 4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfonyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate(prepared as described in Example 42) and(S)-3-mercapto-1-[N-(4-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidine asstarting materials, in relative proportions similar to those used inthat Example, the title compound was obtained in a yield of 39%.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 1769, 1694, 1675,1567, 1520, 1345, 1242, 839.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

0.08 (3H, singlet);

0.09 (3H, singlet);

0.87 (9H, singlet);

1.22-1.31 (6H, multiplet);

1.96-2.16 (1H, multiplet);

2.29 (0.75H, singlet);

2.32 (2.25H, singlet);

2.35-2.51 (1H, multiplet);

3.23-3.35 (2H, multiplet);

3.44-4.05 (5H, multiplet);

4.24-4.32 (2H, multiplet);

5.22 (2H, singlet);

5.24 (1H, doublet, J=14 Hz);

5.45 (1H, doublet, J=14 Hz);

7.56 (2H, doublet, J=9 Hz);

7.65 (2H, doublet, J=9 Hz);

8.19 (2H, doublet, J=9 Hz);

8.21 (2H, doublet, J=9 Hz).

Mass spectrum (m/z): 781 (M⁺, C₃₇ H₄₇ N₅ O₁₀ SSi).

EXAMPLE 22

4-Nitrobenzyl (1R,5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-methyl-2-[2-(4-nitrobenzyloxycarbonyl)aminoethylthio]-1-carbapen-2-em-3-carboxylate##STR64## (a) Following a procedure similar to that described in Example18, but using 4-nitrobenzyl(1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate(prepared as described in Example 39) and2-(4-nitrobenzyloxycarbonyl)aminoethylmercaptan as starting materials,in relative proportions similar to those used in that Example, the titlecompound was obtained as a foam-like solid in a yield of 92%.

(b) Following a procedure similar to that described in Example 21(b),but using 4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate(prepared as described in Example 39) and2-(4-nitrobenzyloxycarbonyl)aminoethylmercaptan as starting materials,in relative proportions similar to those used in that Example, the titlecompound was obtained in a yield of 83%.

(c) Following a procedure similar to that described in Example 21(b),but using the S-oxide isomer of lower polarity of the 4-nitrobenzyl(1R,5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-methyl-2-phenylsulfinyl-1-carbapen-2-em-3-carboxylate(prepared as described in Preparation 2) and2-(4-nitrobenzyloxycarbonyl)aminoethylmercaptan as starting materials,in relative proportions similar to those used in that Example, the titlecompound was obtained in a yield of 81%.

(d) Following the same procedure as that described in (c) above, butusing the corresponding S-oxide of higher polarity, the title compoundwas obtained in a yield of 89%.

(e) Following a procedure similar to that described in Example 19(c),but using 4-nitrobenzyl(1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfonyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate(prepared as described in Example 42) and2-(4-nitrobenzyloxycarbonyl)aminoethylmercaptan as starting materials,in relative proportions similar to those used in that Example, the titlecompound was obtained in a yield of 87%.

(f) Following a procedure similar to that described in Example 19 (c),but using 4-nitrobenzyl(1R,5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-methyl-2-phenylsulfonyl-1-carbapen-2-em-3-carboxylate(prepared as described in Preparation 46) and2-(4-nitrobenzyloxycarbonyl)aminoethylmercaptan as starting materials,in relative proportions similar to those used in that Example, the titlecompound was obtained in a yield of 86%.

(g) 0.14 (0.21 mmol) of a cyclohexane solution containing 1.5M of alithiumdiisopropylamide tetrahydrofuran complex was added to 2 ml of anice-cooled tetrahydrofuran suspension containing 91 mg (0.352 mmol) of amagnesium bromide-diethyl ether complex, and the resulting mixture wasstirred for 10 minutes at this temperature. At the end of this time, 2ml of a tetrahydrofuran solution containing 55 mg (0.207 mmol) of2-(4-nitrobenzyloxycarbonyl)aminoethylmercaptan were added to themixture, which was then stirred for a further 10 minutes in an ice bath.102 mg (0.174 mmol) of the S-oxide isomer of lower polarity of the4-nitrobenzyl(1R,5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-methyl-2-phenylsulfinyl-1-carbapen-2-em-3-carboxylate(prepared as described in Preparation 2) and were then added to themixture, and the mixture was stirred for a further 15 minutes. At theend of this time, a saturated aqueous solution of ammonium chloride wasadded, and then the mixture was extracted with ethyl acetate. Theresulting organic extract was washed first with water and then with asaturated aqueous solution of sodium chloride, after which the solventwas removed by distillation under reduced pressure. The residue waspurified by column chromatography through 15 g of silica gel, using a1:19 by volume mixture of ethyl acetate and hexane as the eluent, togive 104 mg (yield 84%) of the title compound as a foam-like solid.

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻¹ : 1771, 1723,1607, 1522, 1347, 1140.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

0.07 (3H, singlet);

0.08 (3H, singlet);

0.86 (9H, singlet);

1.22-1.28 (6H, multiplet);

2.93 (1H, doublet of triplets, J=13 & 7 Hz);

3.11 (1H, doublet of triplets, J=13 & 7 Hz);

3.26 (1H, doublet of doublets, J=3 & 5 Hz);

3.30-3.60 (3H, multiplet);

4.22-4.31 (2H, multiplet);

5.20 (2H, singlet);

5.25 (1H, doublet, J=14 Hz);

5.35 (1H, dull triplet, J=6 Hz);

5.47 (1H, doublet, J=14 Hz);

7.50 (2H, doublet, J=9 Hz);

7.66 (2H, doublet, J=9 Hz);

8.20 (2H, doublet, J=9 Hz);

8.21 (2H, doublet, J=9 Hz).

Mass spectrum (m/z): 714 (M⁺, C₃₃ H₄₂ N₄ O₁₀ SSi).

EXAMPLE 23

4-Nitrobenzyl (1R,5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-methyl-2-(4-nitrobenzylthio)-1-carbapen-2-em-3-carboxylate ##STR65## (a)Following a procedure similar to that described in Example 1, but using4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate(prepared as described in Example 39) and 4-nitrobenzylmercaptan asstarting materials, in relative proportions similar to those used inthat Example, the title compound was obtained in a yield of 81%.Recrystallization of this product from a mixture of ethyl acetate anddiisopropyl ether the title compound in the form of crystals, melting at150.5° to 151° C.

(c) Following a procedure similar to that described in Example 21(b),but using 4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate(prepared as described in Example 39) and 4-nitrobenzylmercaptan asstaring materials, in relative proportions similar to those used in thatExample, the title compound was obtained in a yield of 88%.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 1773, 1711, 1605,1522, 1345, 1140.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

0.06 (3H, singlet);

0.08 (3H, singlet);

0.85 (9H, singlet);

1.24 (3H, doublet, J=5 Hz);

1.26 (3H, doublet, J=6 Hz);

3.25 (1H, doublet of doublets, J=2 & 5 Hz);

3.30 (1H, doublet of quartets, J=10 & 6 Hz);

4.11-4.23 (3H, multiplet);

4.25 (1H, quint, J=5 Hz);

5.25 (1H, doublet, J=14 Hz);

5.46 (1H, doublet, J=14 Hz);

7.52 (2H, doublet, J=8 Hz);

7.65 (2H, doublet, J=8 Hz);

8.20 (2H, doublet, J=8 Hz);

8.21 (2H, doublet, J=8 Hz).

Mass spectrum (m/z): 627 (M⁺, C₃₀ H₃₇ N₃ O₈ SSi).

EXAMPLE 24

4-Nitrobenzyl (1R,5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-methyl-2-phenylthio-1-carbapen-2-em-3-carboxylate ##STR66##

Following a procedure similar to that described in Example 21(b), butusing 4-nitrobenzyl(1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate(prepared as described in Example 39) and thiophenol as startingmaterials, in relative proportions similar to those used in thatExample, the title compound was obtained as crystals in a yield of 72%.Recrystallization of this product from a mixture of ethyl acetate andhexane afforded crystals of the title compound melting at 149° to 150°C.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 1768, 1694, 1607,1335, 1136, 839.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

0.06 (6H, singlet);

0.84 (9H, singlet);

0.95 (3H, doublet, J=7 Hz);

1.17 (3H, doublet, J=6 Hz);

3.06 (1H, doublet of quartets, J=10 & 7 Hz);

3.19 (1H, doublet of doublets, J=2 & 5 Hz);

4.19 (1H, doublet of doublets, J=2 & 10 Hz);

4.25 (1H, doublet of quartets, J=5 & 6 Hz);

5.33 (1H, doublet, J=14 Hz);

5.50 (1H, doublet, J=14 Hz);

7.37-7.43 (3H, multiplet);

7.51-7.57 (2H, multiplet);

7.69 (2H, doublet, J=8 Hz);

8.22 (2H, doublet, J=8 Hz).

Mass spectrum (m/z): 568 (M⁺, C₂₉ H₃₆ N₂ O₆ SSi).

EXAMPLE 25

4-Nitrobenzyl (1R,5S,6S)-2-[2-(1-perhydroazepinylcarbonyl)phenylthio]-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate##STR67##

Following a procedure similar to that described in Example 18, but using4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate(prepared as described in Example 39) and2-(1-perhydroazepinylcarbonyl)phenylmercaptan as starting materials, inrelative proportions similar to those used in that Example, the titlecompound was obtained in a yield of 72%. The compound was found to bethe same as the compound prepared as described in Example 36 and had thesame physicochemical properties.

EXAMPLE 26

4-Nitrobenzyl(1R,5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-2-ethylthio-1-methyl-1-carbapen-2-em-3-carboxylate##STR68##

Following a procedure similar to that described in Example 18, but using4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate(prepared as described in Example 39) and ethylmercaptan as startingmaterials, in relative proportions similar to those used in thatExample, the title compound was obtained as a crystal in a yield of 83%.Recrystallization of this product from diisopropyl ether afforded thetitle compound in the form of crystals melting at 121°-121.5° C.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 1757, 1700, 1522,1499, 1339, 1215, 1144, 839.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

0.07 (3H, singlet);

0.08 (3H, singlet);

0.86 (9H, singlet);

1.25 (3H, doublet, J=7 Hz);

1.26 (3H, doublet, J=6 Hz);

1.34 (3H, triplet, J=7 Hz);

2.86 (1H, doublet of doublets, J=12 & 7 Hz);

2.90 (1H, doublet of quartets, J=12 & 7 Hz);

3.23 (1H, doublet of doublets, J=3 & 6 Hz);

3.35 (1H, doublet of quartets, J=9 & 7 Hz);

4.20 (1H, doublet of doublets, J=3 & 9 Hz);

4.26 (1H, quartet, J=6 Hz);

5.25 (1H, doublet, J=14 Hz);

5.46 (1H, doublet, J=14 Hz);

7.66 (2H, doublet, J=9 Hz);

8.21 (2H, doublet, J=9 Hz).

Mass spectrum (m/z): 520 (M⁺, C₂₅ H₃₆ N₂ O₆ SSi).

EXAMPLE 27

4-Nitrobenzyl(1R,5S,6S)-2-[(3S,5S)-5-dimethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-3-pyrrolidinylthio]-1-methyl-5-[1(R)-hydroxyethyl]-1-carbapen-2-em-3-carboxylate##STR69## 27(a) 4-Nitrobenzyl(1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-t-hydroxyethyl]-1-carbapen-2-em-3-carboxylate

Following a procedure similar to that described in Example 38, but using467 mg (0.843 mmol) of 4-nitrobenzyl(1R,5S,6S)-2-(2-diethylcarbamoylphenylthio)-1-methyl-6-[1(R)-t-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (prepared asdescribed in Example 37) and 201 mg (0.932 mmol) of m-chloroperbenzoicacid (purity 80%), 464 mg of the title compound were obtained as a crudeproduct. This product was used for the next reaction without furtherpurification.

27(b) 4-Nitrobenzyl(1R,5S,6S)-2-[(3S,5S)-5-diethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-3-pyrrolidinylthio]-1-methyl-6-[1(R)-hydroxyethyl]-1-carbapen-2-em-3-carboxylate

3 ml of a tetrahydrofuran solution containing 347 mg (0.982 mmol) of(2S,4S)-dimethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-4-mercaptopyrrolidinewere cooled in an ice bath, and then 0.97 ml (0.97 mmol) of atetrahydrofuran solution containing 1M of bromo-magnesiumisopropylcyclohexylamide were added dropwise to the cooled solution overa period of 4 minutes, after which the mixture was stirred for 10minutes. 2 ml of a tetrahydrofuran solution containing 464 mg of thecrude 4-nitrobenzyl(1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-hydroxyethyl]-1-carbapen-2-em-3-carboxylateprepared as described in step (a) above was then added to the solution,and the resulting solution was stirred for a further 30 minutes. At theend of this time, a saturated aqueous solution of ammonium chloride wasadded, followed by water, and then the reaction mixture was extractedwith ethyl acetate 3 times. The organic layers were collected, combinedand washed with water and then with a saturated aqueous solution ofsodium chloride. The solvent was then removed by distillation underreduced pressure, and the resulting oily residue was subjected to columnchromatography through 50 g of silica gel. Elution with a 1:9 by volumemixture of methanol and ethyl acetate afforded 365 mg of the titlecompound as a foam-like solid (a yield of 62% in terms of the compoundof Example 37).

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 3500-3300, 1771,1707, 1649, 1522, 1345, 1140, 855.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

1.25 (1.5H, doublet, J=7 Hz);

1.28 (1.5H, doublet, J=7 Hz);

1.34 (3H, doublet, J=6 Hz);

1.86-1.99 (1H, multiplet);

2.40-3.20 (1H, broad);

2.67-2.81 (1H, multiplet);

2.94 (1.5H, singlet);

2.99 (3H, singlet);

3.11 (1.5H, singlet);

3.23-3.29 (1H, multiplet);

3.34-3.76 (3H, multiplet);

4.04-4.29 (3H, multiplet);

4.73 (0.5H, triplet, J=8 Hz);

4.78 (0.5H, triplet, J=8 Hz);

5.07 (0.5H, doublet, J=14 Hz);

5.21 (1H, singlet);

5.22 (0.5H, doublet, J=14 Hz);

5.23 (1H, doublet, J=14 Hz);

5.48 (1H, doublet, J=14 Hz);

7.43 (1H, doublet, J=8 Hz);

7.51 (1H, doublet, J=8 Hz);

7.64 (2H, doublet, J=8 Hz);

8.20 (1H, doublet, J=9 Hz);

8.17-8.22 (3H, multiplet).

EXAMPLE 28

4-Nitrobenzyl(5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-2-[(3S,5S)-5-dimethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-3-pyrrolidinylthio]-1-carbapen-2-em-3-carboxylate ##STR70##

Following a procedure similar to that described in Example 18, but using(2S,4S)-2-dimethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-4-mercaptopyrrolidineand the crude 4-nitrobenzyl(5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-2-phenylsulfinyl-1-carbapen-2-em-3-carboxylate(prepared as described in Preparation 47, but used before purificationby column chromatography) as starting materials, in relative proportionssimilar to those used in that Example, the title compound was obtainedas a foam-like solid in a yield of 89%.

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻¹ : 1179, 1709,1657, 1522, 1345, 1136, 837.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

0.08-0.09 (6H, multiplet);

0.87 (4.5H, singlet);

0.88 (4.5H, singlet);

1.23-1.27 (3H, multiplet);

1.90-2.03 (1H, multiplet);

2.65-2.79 (1H, multiplet);

2.93 (1.5H, singlet);

2.97 (1.5H, singlet);

2.99 (1.5H, singlet);

3.10 (1.5H, singlet);

3.03-3.30 (3H, multiplet);

3.49-3.71 (2H, multiplet);

4.07-4.30 (3H, multiplet);

4.72 (1H, doublet of triplets, J=14 & 8 Hz);

5.07 (0.5H, doublet, J=14 Hz);

5.23 (1H, singlet);

5.25 (1H, doublet, J=14 Hz);

5.30 (0.5H, doublet, J=14 Hz);

5.44 (1H, doublet, J=14 Hz);

7.44 (1H, doublet, J=9 Hz);

7.52 (1H, doublet, J=9 Hz);

7.64 (2H, doublet, J=9 Hz);

8.19-8.24 (4H, multiplet).

EXAMPLE 29

4-Nitrobenzyl(5R,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-2-[(3S,5S)-5-dimethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-3-pyrrolidinylthio]-penem-3-carboxylate ##STR71##

Following a procedure similar to that described in Example 18, but using(2S,4S)-2-dimethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-4-mercaptopyrrolidineand 4-nitrobenzyl(5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-2-ethylsulfinylpenem-3-carboxylate(prepared as described in Preparation 50) as starting materials, inrelative proportions similar to those used in that Example, the titlecompound was obtained as a foam-like solid in a yield of 81%.

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻¹ : 1788, 1711,1657, 1522, 1345, 1117, 839.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

0.04 (3H, singlet);

0.07 (3H, singlet);

0.83 (9H, singlet);

1.25 (3H, doublet, J=6 Hz);

1.91-2.05 (1H, multiplet);

2.67-2.85 (1H, multiplet);

2.93 (1.5H, singlet);

2.97 (1.5H, singlet);

2.99 (1.5H, singlet);

3.09 (1.5H, singlet);

3.46-3.60 (1H, multiplet);

3.69-3.80 (2H, multiplet);

4.22-4.40 (2H, multiplet);

4.68-4.79 (1H, multiplet);

5.07 (0.5H, doublet, J=14 Hz);

5.21 (1H, doublet, J=14 Hz);

5.23 (1H, singlet);

5.31 (0.5H, doublet, J=14 Hz);

5.41 (1H, doublet, J=14 Hz);

5.69 (1H, singlet);

7.44 (1H, doublet, J=9 Hz);

7.52 (1H, doublet, J=9 Hz);

7.61 (2H, doublet, J=9 Hz);

8.19-8.24 (4H, multiplet).

EXAMPLE 30

4-Nitrobenzyl(5R,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-2-[2-(4-nitrobenzyloxycarbonyl)aminoethylthio]-penem-3-carboxylate##STR72## (a) Following a procedure similar to that described in Example18, but using 4-nitrobenzyl(5R,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-2-ethylsulfinylpenem-3-carboxylate(prepared as described in Preparation 50) and2-(4-nitrobenzyloxycarbonyl)aminoethylmercaptan as starting materials,in relative proportions similar to those used in that Example, the titlecompound was obtained as a foam-like solid in a yield of 76%.

(b) Following a procedure similar to that described in Example 21(b),but using 4-nitrobenzyl(5R,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-2-ethylsulfinyl-penem-3-carboxylate (prepared as described in Preparation 50) and2-(4-nitrobenzyloxylcarbonyl)aminoethylmercaptan as starting materials,in relative proportions similar to those used in that Example, the titlecompound was obtained in a yield of 86%.

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻¹ : 1788, 1725,1607, 1522, 1347, 1119.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm:

0.04 (3H, singlet);

0.07 (3H, singlet);

0.83 (9H, singlet);

1.24 (3H, doublet, J=6 Hz);

3.04-3.24 (2H, multiplet);

3.53 (2H, quartet, J=6 Hz);

3.73 (1H, doublet of doublets, J=1 & 4 Hz);

4.36 (1H, doublet of quartets, J=4 & 6 Hz);

5.18-5.27 (1H, multiplet);

5.20 (2H, singlet);

5.21 (1H, doublet, J=14 Hz);

5.42 (1H, doublet, J=14 Hz);

5.67 (1H, doublet, J=1 Hz);

7.50 (2H, doublet, J=9 Hz);

7.62 (2H, doublet, J=9 Hz);

8.20 (2H, doublet, J=9 Hz);

8.22 (2H, doublet, J=9 Hz).

Mass spectrum (m/z): 661 (M⁺ (C₃₁ H₃₈ N₄ O₁₀ S₂ Si)-t-Bu).

EXAMPLE 31

4-Nitrobenzyl(5S,6S)-6-[1(R)-trimethylsiloxyethyl]-2-{(S)-1-[N-(4-nitrobenzyloxycarbonyl)-acetimidoyl]pyrrolidin-3-ylthio}-1-carbapen-2-em-3-carboxylate##STR73## (i) 4-Nitrobenzyl(5S,6S)-6-[1(R)-hydroxyethyl]-2-[2-(4-nitrobenzyloxycarbonyl)aminoethylthio]-1-carbapen-2-em-3-carboxylatewas prepared in two steps from thienamycin following the proceduredescribed by S. M. Schmitt et al. [J. Org. Chem. (1980), 45, 1142]. 140mg (0.239 mmol) of this compound were then dissolved in 2 ml oftetrahydrofuran, and 0.233 ml (1.65 mmol) of triethylamine and 0.147(1.19 mmol) of trimethylsilyl chloride were added to the solution; theresulting mixture was then stirred for 9 hours. Because the startingmaterial did not disappear, a further 0.167 ml (1.20 mmol) oftriethylamine and 0.148 ml (1.20 mmol) of trimethylsilyl chloride wereadded, and the mixture was stirred for a further 1 hour. At the end ofthis time, the reaction solution was diluted with ethyl acetate, andwashed with ice water and then dried with a saturated aqueous solutionof sodium chloride. The solvent was then removed by distillation underreduced pressure. The resulting residue was purified by columnchromatography through 10 g of silica gel. Elution with a 15:85 byvolume mixture of ethyl acetate and methylene chloride yielded 130 mg(83%) of a trimethylsilyl compound in the form of crystals.Recrystallization of these from a mixture of ethyl acetate and hexaneafforded crystals of the trimethylsilyl compound melting at 165° to 168°C.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 1773, 1738, 1694,1607, 1518, 1341, 1140.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

0.14 (9H, singlet);

1.28 (3H, doublet, J=6 Hz);

2.91-3.18 (3H, multiplet);

3.16 (1H, doublet of doublets, J=2 & 6 Hz);

3.27-3.49 (3H, multiplet);

4.11-4.26 (2H, multiplet);

5.20 (2H, singlet);

5.25 (1H, doublet, J=14 Hz);

5.15-5.30 (1H, multiplet);

5.48 (1H, doublet, J=14 Hz);

7.50 (2H, doublet, J=9 Hz);

7.66 (2H, doublet, J=9 Hz);

8.21 (2H, doublet, J=9 Hz);

8.23 (2H, doublet, J=9 Hz).

(ii) Following a procedure similar to that described in Example 38, butusing 130 mg of the trimethylsilyl compound obtained as described instep (i) above, 137 mg of a crude S-oxide were obtained.

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻¹ : 1786, 1721,1607, 1522, 1349, 1252, 1053.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

0.13 (9H, singlet);

1.25 (1.5H, doublet, J=6 Hz);

1.26 (1.5H, doublet, J=6 Hz);

3.03-3.38 (4.5H, multiplet);

3.52-3.85 (2.5H, multiplet);

4.20-4.45 (2H, multiplet);

5.20 (1H, singlet);

5.22 (1H, singlet);

5.26 (0.5H, doublet, J=14 Hz);

5.30 (0.5H, doublet, J=14 Hz);

5.43 (0.5H, doublet, J=14 Hz);

5.47 (0.5H, doublet, J=14 Hz);

5.62-5.70 (1H, multiplet);

7.51 (2H, doublet, J=9 Hz);

7.62 (1H, doublet, J=9 Hz);

7.65 (1H, doublet, J=9 Hz);

8.22 (2H, doublet, J=9 Hz);

8.23 (2H, doublet, J=9 Hz).

(iii) Following a procedure similar to that described in Example 18, butusing 137 mg of the crude S-oxide obtained as described in step (ii)above and 84 mg of(S)-3-mercapto-1-[N-(4-nitrobenzyloxycarbonyl)acetimidoyl]pyrrolidine,126 mg (a yield of 87% calculated in terms of the trimethylsilylderivative) of the title compound was obtained as crystals.Recrystallization of these from a mixture of ethyl acetate and hexaneafforded crystals of the title compound melting at 95° to 96° C. Thephysicochemical properties of this compound accorded with those of thecompound reported by A. Yoshida et al. [Tetrahedron Letters 255, 2793(1984)].

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻¹ : 1783, 1700,1676, 1557, 1520, 1349, 1239, 845.

Nuclear Magnetic Resonance Spectrum (CDCl₃), δ ppm:

0.14 (2.25H, singlet);

0.15 (6.75H, singlet);

1.29 (3H, doublet, J=6 Hz);

1.96-2.17 (1H, multiplet);

2.29 (0.75H, singlet);

2.32 (2.25H, singlet);

2.30-2.51 (1H, multiplet);

3.06-3.31 (3H, multiplet);

3.45-4.07 (5H, multiplet);

4.15-4.27 (2H, multiplet);

5.23 (2H, singlet);

5.24 (1H, doublet, J=14 Hz);

5.48 (1H, doublet, J=14 Hz);

7.56 (2H, doublet, J=9 Hz);

7.65 (2H, doublet, J=9 Hz);

8.20 (2H, doublet, J=9 Hz);

8.22 (2H, doublet, J=9 Hz).

EXAMPLE 32

4-Nitrobenzyl (1R,5S,6S)-6-2-{(3(S)-(4-nitrobenzyloxycarbonyl)aminopyrrolidin-1-ylcarbonyl]-1-methylpyrrolidin-3-ylthio}-6-[1(R)-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate ##STR74##

Following a procedure similar to that described in Example 27(b), butusing 4-nitrobenzyl(1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-hydroxyethyl]-1-carbapen-2-em-3-carboxylate [prepared asdescribed in Example 27(a)] and(2S,4S)-4-mercapto-2-[3(S)-4-nitrobenzyloxycarbonyl)aminopyrrolidin-1-ylcarbonyl]-1-methylpyrrolidine as starting materials,in relative proportions similar to those used in that Example, the titlecompound was obtained as a powder in a yield of 60%.

The physicochemical properties of this compound were in agreement withthose of the intermediate 45(a) described in Example 45 of EuropeanPatent Publication No. 518 558A.

EXAMPLE 33

4-Nitrobenzyl(1R,5S,6S)-2-[(RS)-5-oxo-3-pyrrolidinylthio]-6-[1(R)-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate##STR75##

Following a procedure similar to that described in Example 27(b), butusing 4-nitrobenzyl(1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-hydroxyethyl]-1-carbapen-2-em-3-carboxylate [prepared asdescribed in Example 27(a)] and 4-mercapto-2-oxo-pyrrolidine as startingmaterials, in relative proportions similar to those used in thatExample, the title compound was obtained as a powder in a yield of 59%.

The physicochemical properties of this compound were in agreement withthose of the intermediate described in Example 11 of Japanese PatentPublication No. Hei 2-49783.

EXAMPLE 34

4-Nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylthio)-1-methyl-6-[1(R)-trimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate##STR76##

8 ml of methylene chloride solution containing 492 mg (1.09 mmol) ofS-2-diethylcarbamoylphenyl2(R)-[(2S,3S)-3-[1(R)-(trimethylsilyloxy)ethyl]-4-oxo-2-azetidinyl]thiopropionate(prepared as described in Preparation 1) and 0.46 ml (3.30 mmol) oftriethylamine were cooled in a salt-ice bath, and then 797 mg (3.27mmol) of p-nitrobenzyloxyoxalyl chloride were added to the solution. Theresulting mixture was then allowed to react for 15 minutes at thistemperature. At the end of this time, 0.25 ml (3.27 mmol) of isopropanolwas added, and the reaction mixture was stirred for 10 minutes at thistemperature to decompose any excess of the acid chloride. The reactionsolution was then diluted with ethyl acetate, and washed twice withwater and then twice with a saturated aqueous solution of sodiumchloride. The solvent was then removed by distillation under reducedpressure. The resulting residue was suspended in toluene, and insolublematter was filtered off. Toluene was then removed by distillation underreduced pressure, 784 mg (4.40 mmol) of dipropyl ethylphosphonite wereadded to the residue, and the mixture was stirred for 140 minutes atroom temperature. At the end of this time, excess reagent was removed bydistillation under reduced pressure, and the residue was dissolved in 65ml of xylene and heated under reflux for 3 hours. The solvent was thenremoved by distillation under reduced pressure, and the resultingresidue was purified by column chromatography through 50 g of silicagel. The title compound containing a small amount of impurities wasobtained by elution with a 1:2 by volume mixture of ethyl acetate andhexane. Further purification by column chromatography under the sameconditions yielded 535 mg (78%) of the title compound. Recrystallizationof this product from diisopropyl ether afforded the title compound inthe form of colorless crystals melting at 202°-203° C.

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻¹ : 1761, 1695,1630, 1342, 1207.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

0.10 (9H, singlet);

1.01 (3H, triplet, J=7 Hz)

0.29-1.20 (6H, multiplet);

1.20 (3H, doublet, J=6 Hz);

3.06 (2H, quartet, J=7 Hz);

3.05-3.28 (3H, multiplet);

3.45-3.80 (1H, broad singlet);

4.18-4.25 (2H, multiplet);

5.27 (1H, doublet, J=14 Hz);

5.47 (1H, doublet, J=14 Hz);

7.32-7.65 (4H, multiplet);

7.68 (2H, doublet, J=9 Hz);

8.21 (2H, doublet, J=9 Hz).

Mass spectrum (m/z): 625 (M⁺, C₃₁ H₃₉ N₃ O₇ SSi).

EXAMPLE 35

4-Nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylthio)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate##STR77##

Following a procedure similar to that described in Example 34, but usingS-2-diethylcarbamoylphenyl2(R)-[(2S,3S)-3-[1(R)-t-butyldimethylsilyloxyethyl]-4-oxo-2-azetidinyl]thiopropionate(prepared as described in Preparation 52 of this specification and alsoin Example 1 of Japanese Patent Application No. Hei 4-174099) as astarting material, in a relative amount similar to that used in thatExample, the title compound was obtained in a yield of 80%.Recrystallization of this product from dissopropyl ether afforded thetitle compound in the form of crystals melting at 166°-166.5° C.

Infrared Absorption Spectrum (Nujol-trade mark), ν_(max) cm⁻¹ : 1762,1693, 1633, 1340, 1210.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

0.06 (6H, singlet);

0.84 (9H, singlet);

1.01 (3H, triplet, J=7 Hz);

0.93-1.20 (6H, multiplet);

1.16 (3H, doublet, J=6 Hz);

3.00-3.30 (3H, multiplet);

3.07 (2H, quartet, J=7 Hz);

3.40-3.90 (1H, multiplet);

4.21-4.33 (2H, multiplet);

5.28 (1H, doublet, J=14 Hz);

5.44 (1H, doublet, J=14 Hz);

7.27-7.65 (4, multiplet);

7.67 (2H, doublet, J=9 Hz);

8.21 (2H, doublet, J=9 Hz).

Mass spectrum (m/z): 667 (M⁺, C₃₄ H₄₅ N₃ O₇ SSi).

EXAMPLE 36

4-Nitrobenzyl (1R,5S,6S)-2-[2-(1-perhydroazepinylcarbonyl)phenylthio]-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate##STR78##

Following a procedure similar to that described in Example 34, but usingS-2-(1-perhydroazepinylcarbonylphenyl2(R)-{(2S,3S)-3-[1(R)-t-butyldimethylsilyloxyethyl]-4-oxo-2-azetidinyl}thiopropionate(prepared as described in Example 9 of Japanese Patent Application No.Hei 5-174099) as a starting material, in a relative amount similar tothat used in that Example, the title compound was obtained in a yield of70%. Recrystallization of this product from diisopropyl ether gave thetitle compound in the form of crystals melting at 210°-211° C.

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻¹ : 1757, 1700, 1632,1341, 1212, 1138.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

0.06 (6H, singlet);

0.85 (9H, singlet);

0.95-1.08 (3, multiplet);

1.16 (3H, doublet, J=6 Hz);

1.40-1.85 (8H, multiplet);

3.04-3.34 (5H, multiplet);

3.45-3.65 (1H, broad singlet);

4.20-4.36 (2H, multiplet);

5.29 (1H, doublet, J=14 Hz);

5.46 (1H, doublet, J=14 Hz);

7.30-7.65 (4H, multiplet);

7.68 (2H, doublet, J=9 Hz);

8.22 (2H, doublet, J=9 Hz).

Mass spectrum (m/z): 693 (M⁺, C₃₆ H₄₇ N₃ O₇ SSi).

EXAMPLE 37

4-Nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylthio)-1-methyl-6-[1(R)-hydroxyethyl]-1-carbapen-2-em-3-carboxylate ##STR79##

41 mg (0.195 mmol) of citric acid hydrate were added to 30 ml of asolution of 1.072 g (1.71 mmol) of 4-nitrobenzyl(1R,5S,6S)-2-(2-diethylcarbamoylphenylthio)-1-methyl-6-[1(R)-trimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate(prepared as described in Example 34) in a 2:1 by volume mixture ofmethanol and methylene chloride, and the mixture was stirred for 20minutes at room temperature. At the end of this time, the reactionsolution was condensed by distillation under reduced pressure. Theresulting residue was purified by column chromatography through 25 g ofsilica gel. Elution with ethyl acetate afforded 970 mg (quantitativeyield) of the title compound as a colorless foam-like solid.

Infrared Absorption Spectrum (neat), ν_(max) cm⁻¹ : 3600-3200 (broad),1771, 1707, 1612, 1345, 1207.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

1.00 (3H, triplet, J=7 Hz);

0.94-1.15 (6H, multiplet);

1.30 (3H, doublet, J=6 Hz);

3.05 (2H, quartet, J=7 Hz);

3.10-3.28 (3H, multiplet);

3.45-3.80 (1H, broad singlet);

4.20 (1H, quintet, J=7 Hz);

4.25 (1H, doublet of doublets, J=2 & 9 Hz);

5.27 (1H, doublet, J=14 Hz);

5.48 (1H, doublet, J=14 Hz);

7.31-7.65 (4H, multiplet);

7.67 (2H, doublet, J=9 Hz);

8.22 (2H, doublet, J=9 Hz).

Mass spectrum (m/z): 553 (M⁺, C₂₈ H₃₁ N₃ O₇ S).

EXAMPLE 38

4-Nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-trimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate##STR80##

122 mg (1.45 mmol) of sodium hydrogencarbonate were added to 6 ml of amethylene chloride solution containing 304 mg (0.486 mmol) of4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylthio)-1-methyl-6-[1(R)-trimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate(prepared as described in Example 34). The mixture was then placed in anice bath while 105 mg (0.487 mmol) of m-chloroperbenzoic acid (80%purity) were added, with stirring. The reaction mixture was stirred for1 hour at the same temperature, after which it was diluted withmethylene chloride and washed with an ice-cooled dilute aqueous solutionof sodium hydrogencarbonate. The solvent was then removed bydistillation under reduced pressure. The resulting residue was purifiedby column chromatography through 25 g of silica gel. Elution with a 2:1by volume mixture of ethyl acetate and hexane afforded 260 mg (yield83%) of the title compound as a foam-like solid.

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻¹ : 1788, 1734,1630, 1522, 1061.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

0.08 (5.4H, singlet);

0.10 (3.6H, singlet);

1.04-1.27 (12H, multiplet);

2.98-3.53 (5.6H, multiplet);

3.67 (0.4H, doublet of quartets, J=11 & 7 Hz);

4.16-4.23 (1H, multiplet);

4.26 (0.6H, doublet of doublets, J=10 & 3 Hz);

4.34 (0.4H, doublet of doublets, J=10 & 3 Hz);

5.35 (0.4H, doublet, J=14 Hz);

5.38 (0.6H, doublet, J=14 Hz);

5.46 (0.4H, doublet, J=14 Hz);

5.50 (0.6H, doublet, J=14 Hz);

7.27-7.36 (1H, multiplet);

7.50-7.73 (4H, multiplet);

7.84-7.90 (0.4H, multiplet);

8.15-8.26 (2.6H, multiplet).

Mass spectrum (m/z): 641 (M⁺, C₃₁ H₃₉ N₃ O₈ SSi).

EXAMPLE 39

4-Nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate##STR81##

Following a procedure similar to that described in Example 38, but using4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylthio)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate(prepared as described in Example 35) as a starting material, in arelative amount similar to that used in that Example, the title compoundwas obtained as a foam-like solid in a yield of 87%.

Infrared Absorption Spectrum (Nujol), ν_(max) cm⁻¹ : 1788, 1735, 1630,1523, 1058.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

0.03-0.06 (6H, multiplet);

0.83 (4.5H, singlet);

0.84 (4.5H, singlet);

1.05-1.27 (12H, multiplet);

2.98-3.56 (5.5H, multiplet);

3.59 (0.5H, doublet of quartets, J=10 & 7 Hz);

4.20-4.38 (1H, multiplet);

4.30 (0.5H, doublet of doublets, J=11 & 3 Hz);

4.39 (0.5H, doublet of doublets, J=11 & 3 Hz);

5.34 (0.5H, doublet, J=14 Hz);

5.38 (0.5H, doublet, J=14 Hz);

5.45 (0.5H, doublet, J=14 Hz);

5.49 (0.5H, doublet, J=14 Hz);

7.29-7.36 (1H, multiplet);

7.50-7.71 (4H, multiplet);

7.85-7.89 (0.5H, multiplet);

8.15-8.25 (2.5H, multiplet).

Mass spectrum (m/z): 683 (M⁺, C₃₄ H₄₅ N₃ O₈ SSi).

EXAMPLE 40

4-Nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-[1(R)-hydroxyethyl]-1-carbapen-2-em-3-carboxylate ##STR82##

10 ml of a methylene chloride solution containing 554 mg (1.00 mmol) of4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylthio)-1-methyl-6-[1(R)-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (preparedas described in Example 37) were cooled in an ice bath, and then 1.5 ml(1.5 mmol) of a 1m aqueous solution of sodium hydrogencarbonate and then215 mg (1.00 mmol) of m-chloroperbenzoic acid (80% purity) were added,and the reaction solution was stirred for 90 minutes at the sametemperature. At the end of this time, an aqueous solution of sodiumsulfite was added to the reaction solution, and the mixture was stirredfor 10 minutes to complete the reaction. The reaction solution was thendiluted with methylene chloride, ice-cooled, washed with an aqueoussolution of sodium hydrogencarbonate and condensed by evaporation underreduced pressure. The resulting residue was purified by columnchromatography through 50 g of silica gel. Elution with ethyl acetateafforded 145 mg (yield 25%) of an isomer of the title compound of lowerpolarity (the isomer is a result of the configuration of the S-oxide),followed by 96 mg (yield 17%) of a higher polarity isomer of the titlecompound, both as foam-like solids.

Lower Polarity S-Oxide

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻ : 3500-3300,1786, 1732, 1624, 1522, 1200, 1061.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

1.02-1.11 (6H, multiplet);

1.24 (6H, triplet, J=7 Hz);

3.01 (1H, doublet of quartets, J=10 & 7 Hz);

3.12 (2H, quartet, J=7 Hz);

3.18-3.30 (1H, multiplet);

3.32 (1H, doublet of doublets, J=3 & 6 Hz);

3.39-3.52 (1H, multiplet);

4.19 (1H, quintet, 6 Hz);

4.28 (1H, doublet of doublets, J=3 & 10 Hz);

5.38 (1H, doublet, J=14 Hz);

5.52 (1H, doublet, J=14 Hz);

7.33 (1H, doublet of doublets, J=1 & 8 Hz);

7.58 (1H, doublet of triplets, J=1 & 8 Hz);

7.66 (1H, doublet of triplets, J=1 & 8 Hz);

7.70 (2H, doublet, J=9 Hz);

8.16 (1H, doublet of doublets, J=1 & 8 Hz);

8.24 (2H, doublet, J=9 Hz).

Higher Polarity S-Oxide

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻ : 3500-3300,1786, 1734, 1624, 1522, 1198, 1061.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

0.83 (3H, doublet, J=7 Hz);

1.09 (3H, triplet, J=7 Hz);

1.18 (3H, triplet, J=7 Hz);

1.28 (3H, doublet, J=6 Hz);

3.18 (2H, quartet, J=7 Hz);

3.20-3.35 (1H, multiplet);

3.40-3.53 (1H, multiplet);

3.47 (1H, doublet of doublets, J=3 & 6 Hz);

3.70 (1H, doublet of quartets, J=10 & 7 Hz);

4.25 (1H, quintet, 6 Hz);

4.38 (1H, doublet of doublets, J=3 & 10 Hz);

5.34 (1H, doublet, J=13 Hz);

5.48 (1H, doublet, J=13 Hz);

7.28-7.32 (1H, multiplet);

7.48-7.56 (2H, multiplet);

7.65 (2H, doublet, J=9 Hz);

7.85-7.91 (1H, multiplet);

8.22 (2H, doublet, J=9 Hz).

Mass spectrum (m/z): 551 [M⁺ (C₂₈ H₃₁ N₅ O₈ S).H₂ O].

EXAMPLE 41

4-Nitrobenzyl (1R,6S,6S)-2-[2-(1-perhydroazepinylcarbonyl)phenylsulfinyl]-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate##STR83##

Following a procedure similar to that described in Example 38, but using4-nitrobenzyl (1R,5S,6S)-2-[2-(1-perhydroazepinylcarbonyl)phenylthio]-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate(prepared as described in Example 36) as a starting material, in arelative amount similar to that used in that Example, the title compoundwas obtained as a foam-like solid in a yield of 89%.

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻ : 1790, 1734,1628, 1524, 1347, 1061.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

0.03, 0.04, 0.05, 0.06 (total 6H, each singlet);

0.75 (1.5H, doublet, J=7 Hz);

0.83 (4.5H, singlet);

0.84 (4.5H, singlet);

1.13 (1.5H, doublet, J=6 Hz);

1.16 (1.5H, doublet, J=6 Hz);

1.28 (1.5H, doublet, J=7 Hz);

1.44-1.80 (8H, multiplet);

3.00 (0.5H, doublet of quartets, J=10 & 7 Hz);

3.11-3.37 (3.5H, multiplet);

3.41-3.50 (1H, multiplet);

3.60-3.77 (1H, multiplet);

4.19-4.31 (1.5H, multiplet);

4.38 (0.5H, doublet of doublets, J=10 & 3 Hz);

5.33 (0.5H, doublet, J=14 Hz);

5.40 (0.5H, doublet, J=14 Hz);

5.46 (0.5H, doublet, J=14 Hz);

5.49 (0.5H, doublet, J=14 Hz);

7.27-7.32 (0.5H, multiplet);

7.36 (0.5H, doublet of doublets, J=7 & 1 Hz);

7.48-7.60 (1.5H, multiplet);

7.63-7.73 (2.5H, multiplet);

7.93-7.96 (0.5H, multiplet);

8.15 (0.5H, doublet of doublets, J=8 & 1 Hz);

8.22 (1H, doublet, J=9 Hz);

8.23 (1H, doublet, J=9 Hz).

Mass spectrum (m/z): 709 (M⁺, C₃₆ H₄₇ N₃ O₈ SSi).

EXAMPLE 42

4-Nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylsulfonyl)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate##STR84##

3 ml of a methylene chloride solution containing 157 mg (0.235 mmol) of4-nitrobenzyl (1R,5S,6S)-2-(2-diethylcarbamoylphenylthio)-1-methyl-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate(prepared as described in Example 35) was cooled in an ice bath, and 78mg (0.93 mmol) of sodium hydrogencarbonate and then 78 mg (0.52 mmol) ofm-chloroperbenzoic acid (80% purity) were added to the cooled solution.The reaction mixture was then stirred for 20 minutes at the sametemperature and for 3.5 hours at room temperature. At then end of thistime, an aqueous solution of sodium sulfite was added to the reactionmixture, and the mixture was stirred for 10 minutes to complete thereaction. The reaction solution was then diluted with methylenechloride, washed with an aqueous solution of sodium hydrogencarbonateand condensed with evaporation under reduced pressure. The resultingresidue was purified by column chromatography through 15 g of silicagel. Elution with a 4:6 by volume mixture of ethyl acetate and hexaneafforded 148 mg (yield 90%) of the title compound as a foam-like solid.

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻ : 1794, 1748,1636, 1524, 1320, 1266, 1161.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

0.03 (3H, singlet);

0.05 (3H, singlet);

0.83 (9H, singlet);

1.06 (3H, triplet, J=7 Hz);

1.16 (3H, doublet, J=6 Hz);

1.20-1.43 (6H, multiplet);

3.01-3.19 (2H, multiplet);

3.24-3.84 (4H, multiplet);

4.19-4.28 (1H, multiplet);

4.42-4.52 (1H, multiplet);

5.39 (2H, singlet);

7.25-7.34 (1H, singlet);

7.48-7.65 (2H, multiplet);

7.62 (2H, doublet, J=9 Hz);

8.11 (1H, doublet, J=8 Hz);

8.21 (2H, doublet, J=9 Hz).

Mass spectrum (m/z): 700 [M⁺ (C₃₄ H₄₅ N₃ O₉ Ssi)+1].

PREPARATION 44

S-2-Diethylcarbamoylphenyl 2(R)-[(2S,3S)-3-(1 R)-(trimethylsilyloxy)ethyl]-4-oxo-3-azetidinyl)-thiopropionate ##STR85##

5 ml of 2N aqueous hydrochloric acid were added to 20 ml of atetrahydrofuran solution containing 1.002 g (2.03) ofS-2-diethylcarbamoylphenyl 2(R)-[(2S,3S)-3-(1R)-t-butyldimethylsilyloxyethyl]-4-oxo-2-azetidinyl]-thiopropionate(prepared as described in Preparation 52 of this specification and alsoin Example 1 of Japanese Patent Application No. Hei 4-174099), and themixture was heated for 3 hours at 50° C. At the end of this time, thereaction solution was cooled and extracted with ethyl acetate. Theorganic extract was washed with a saturated aqueous solution of sodiumhydrogencarbonate, with water and then with a saturated aqueous solutionof sodium chloride, in that order, after which the solvent was removedby distillation under reduced pressure. The resulting desilylatedcompound was dissolved in 10 ml of tetrahydrofuran, and 0.60 ml (4.30mmol) of triethylamine and 0.53 ml of trimethylsilyl chloride were addedto the resulting solution. The reaction mixture was then stirred for 80minutes at room temperature and then for 100 minutes at 40° C. At theend of this time, the reaction mixture was cooled, diluted with ethylacetate and washed with twice ice water and then once with a saturatedaqueous solution of sodium chloride. The solvent was then removed bydistillation under reduced pressure. The resulting residue was purifiedby column chromatography through 50 g of silica gel, using a gradientelution method, with mixtures of ethyl acetate and hexane in ratiosranging from 3:2 to 4:1 by volume as the eluent, to give 742 mg (yield81%) of the title compound as a foam-like solid.

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻ : 3250, 1760,1700, 1625.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

0.12 (9H, singlet);

1.03 (3H, triplet, J=7 Hz);

1.23 (3H, doublet, J=6 Hz);

1.25 (3H, triplet, J=7 Hz);

1.22-1.31 (3H, multiplet);

2.95-3.12 (4H, multiplet);

3.25-3.85 (2H, multiplet);

3.90 (1H, doublet of doublets, J=2 & 4 Hz);

4.14 (1H, quintet, J=6 Hz);

6.07-6.18 (1H, broad singlet);

7.32-7.35 (1H, multiplet);

7.41-7.51 (3H, multiplet).

Mass spectrum (m/z): 450 (M⁺, C₂₂ H₃₄ N₂ O₄ Ssi).

EXAMPLE 45

4-Nitrobenzyl(1R,5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-methyl-2-phenylsulfinyl-1-carbapen-2-em-3-carboxylate##STR86##

Following a procedure similar to that described in Example 38, but using4-nitrobenzyl(1R,5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-methyl-2-phenylthio-1-carbapen-2-em-3-carboxylate(prepared as described in Example 24) as a starting material, in arelative amount similar to that used in that Preparation, and thenpurifying the product by silica gel column chromatography, using agradient elution method, with mixtures of diethyl ether and methylenechloride in ratios ranging from 5:95 to 20:80 by volume as the eluent,the lower polarity S-oxide was obtained as crystals in a yield of 62%,and the higher polarity S-oxide was obtained as a foam-like solid in ayield of 30%.

Recrystallization of the lower polarity S-oxide from a mixture of ethylacetate and hexane afforded crystals of that isomer melting at 150°-151°C.

Isomer of Lower Polarity

Infrared Absorption Spectrum (Kbr), ν_(max) cm⁻ : 1796, 1715, 1528,1335, 1044, 839.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

0.06 (3H, singlet);

0.77 (3H, singlet);

0.73 (3H, doublet, J=7 Hz);

0.85 (9H, singlet);

1.18 (3, doublet, J=6 Hz);

3.27 (1H, doublet of doublets, J=3 & 5 Hz);

3.90 (1H, doublet of quartets, J=11 & 7 Hz);

4.23 (1H, doublet of quartets, J=5 & 6 Hz);

4.41 (1H, doublet of doublets, J=3 & 11 Hz);

5.36 (1H, doublet, J=14 Hz);

5.56 (1H, doublet, J=14 Hz);

7.46-7.53 (3H, multiplet);

7.66 (2H, doublet, J=9 Hz);

7.72-7.78 (2H, multiplet);

8.24 (2H, doublet, J=9 Hz).

Isomer of Higher Polarity

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻ : 1788, 1730,1524, 1319, 1273, 1047, 837.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

0.04 (3H, singlet);

0.05 (3H, singlet);

0.83 (9H, singlet);

1.15 (3H, doublet, J=6 Hz);

1.39 (3H, triplet, J=7 Hz);

3.16 (1H, doublet of quartets, J=10 & 7 Hz);

3.39 (1H, doublet of doublets, J=3 & 4 Hz);

4.16 (1H, doublet of doublets, J=3 & 10 Hz);

4.26 (1H, doublet of quartets, J=4 & 6 Hz);

5.40 (1H, doublet, J=14 Hz);

5.49 (1H, doublet, J=14 Hz);

7.51-7.58 (3H, multiplet);

7.68 (2H, doublet, J=9 Hz);

7.68-7.73 (2, multiplet);

8.23 (2H, doublet, J=9 Hz).

Mass spectrum (m/z): both isomers: 584 (M⁺, C₂₉ H₃₆ N₂ O₇ SSi).

PREPARATION 46

4-Nitrobenzyl(1R,5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-methyl-2-phenylsulfonyl-1-carbapen-2-em-3-carboxylate##STR87##

Following a procedure similar to that described in Example 28, but usingthe isomer of higher polarity of 4-nitrobenzyl(1R,5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-methyl-2-phenylsulfinyl-1-carbapen-2-em-3-carboxylate(prepared as described in Preparation 45) as a starting material, in arelative amount similar to that used in that Preparation, the titlecompound was obtained as a foam-like solid in a yield of 87%.

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻ : 1796, 1750,1524, 1316, 1264, 1161, 1079, 837.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

0.03 (3H, singlet);

0.05 (3H, singlet);

0.84 (9H, singlet);

1.16 (3H, doublet, J=6 Hz);

1.19 (3H, doublet, J=7 Hz);

3.40 (1H, doublet, J=11 & 7 Hz);

3.46-3.52 (1H, multiplet);

4.23 (1H, doublet of quartets, J=4 & 6 Hz);

4.44 (1H, doublet of doublets, J=4 & 11 Hz);

5.45 (2H, singlet);

7.51-7.58 (2H, multiplet);

7.60-7.68 (3H, multiplet);

8.00 (2H, doublet, J=9 Hz);

8.23 (2H, doublet, J=9 Hz).

Mass spectrum (m/z): 543 [M⁺ (C₂₉ H₃₆ N₂ O₈ SSi)-t-Bu].

PREPARATION 47

4-Nitrobenzyl(5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-2-phenylsulfinyl-1-carbapen-2-em-3-carboxylate##STR88##

Following a procedure similar to that described in Example 38 but using4-nitrobenzyl(5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-2-phenylthio-1-carbapen-2-em-3-carboxylate[Tetrahedron Letters 25, 2793 (1984)] as a starting material, in arelative amount similar to that used in that Example. The product wasseparated and purified by silica gel column chromatography eluted with a4:6 by volume mixture of ethyl acetate and hexane, to give the lowerpolarity S-oxide as crystals in a yield of 43%, and the higher polarityS-oxide as a foam-like solid in a yield of 48%. Recrystallization of thelower polarity S-oxide from diisopropyl ether afforded it in the form ofcrystals melting at 111.5°-114° C.

Isomer of Lower Polarity

Infrared Absorption Spectrum (KBr), ν_(max) cm⁻ : 1786, 1723, 1607,1526, 1323, 1206, 1044, 837.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

0.05 (3H, singlet);

0.06 (3H, singlet);

0.85 (9H, singlet);

1.17 (3H, doublet, J=6 Hz);

2.55 (3H, doublet of doublets, J=9 & 18 Hz);

3.08 (1H, doublet of doublets, J=3 & 5 Hz);

3.51 (1H, doublet of doublets, J=11 & 18 Hz);

4.18 (1H, doublet of quartets, J=5 & 6 Hz);

4.37 (1H, doubled doublet of doublets, J=3, 9 & 11 Hz);

5.37 (1H, doublet, J=14 Hz);

5.54 (1H, doublet, J=14 Hz);

7.48-7.54 (3H, multiplet);

7.65 (2H, doublet, J=9 Hz);

7.70-7.77 (2H, multiplet);

8.24 (2H, doublet, J=9 Hz).

Mass spectrum (m/z): 570 (M⁺, C₂₈ H₃₄ N₂ O₇ SSi).

Isomer of Higher Polarity

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻ : 1790, 1723,1607, 1524, 1322, 1269, 1044, 837.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

0.05 (3H, singlet);

0.06 (3H, singlet);

0.84 (9H, singlet);

1.18 (3H, doublet, J=6 Hz);

2.80 (3H, doublet of doublets, J=11 & 19 Hz);

3.29 (1H, doublet of doublets, J=8 & 19 Hz);

3.34 (1H, triplet, J=3 Hz);

4.17-4.30 (2H, multiplet);

5.40 (1H, doublet, J=14 Hz);

5.49 (1H, doublet, J=14 Hz);

7.49-7.55 (3H, multiplet);

7.68 (2H, doublet, J=9 Hz);

7.70-7.76 (2H, multiplet);

8.23 (2H, doublet, J=9 Hz).

PREPARATION 48

4-Nitrobenzyl(1R,5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-methyl-2-[2-(4-nitrobenzyloxycarbonyl)-aminoethylsulfinyl]-1-carbapen-2-em-3-carboxylate##STR89##

Following a procedure similar to that described in Example 38, but using4-nitrobenzyl(1R,5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-methyl-2-[2-(4-nitrobenzyloxycarbonyl)-aminoethylthio]-1-carbapen-2-em-3-carboxylate(prepared as described in Example 22) as a starting material, in arelative amount similar to that used in that Example, the title compoundwas obtained as a foam-like solid in a yield of 92%.

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻ : 1786, 1721,1607, 1522, 1347, 1254, 1048.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

0.07 (3H, singlet);

0.09 (3H, singlet);

0.86 (9H, singlet);

1.23 (1.5H, doublet, J=6 Hz);

1.24 (1.5H, doublet, J=6 Hz);

1.39 (1.5H, doublet, J=7 Hz);

1.40 (1.5H, doublet, J=7 Hz);

3.12-3.45 (3H, multiplet);

3.60-3.92 (3H, multiplet);

4.29 (1H, quartet, J=6 Hz);

4.34 (0.5H, doublet of doublets, J=3 & 10 Hz);

4.46 (0.5H, doublet of doublets, J=3 & 10 Hz);

5.14-5.46 (2H, multiplet);

5.23 (2H, singlet);

5.68-5.77 (1H, multiplet);

7.51 (1H, doublet, J=9 Hz);

7.52 (1H, doublet, J=9 Hz);

7.61 (1H, doublet, J=9 Hz);

7.66 (1H, doublet, J=9 Hz);

8.20-8.24 (4H, multiplet).

Mass spectrum (m/z): 705 [M⁺ (C₃₃ H₄₂ N₄ O₁₁ SSi)-CH₃ ].

PREPARATION 49

4-Nitrobenzyl(1R,5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-1-methyl-2-ethylsulfinyl-1-methyl-1-carbapen-2-em-3-carboxylate##STR90##

Following a procedure similar to that described in Example 38, but using4-nitrobenzyl(1R,5S,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-2-ethylthio-1-methyl-1-carbapen-2-em-3-carboxylate(prepared as described in Example 26) as a starting material, in arelative amount similar to that used in that Example, the title compoundwas obtained as a foam-like solid in a yield of 92%.

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻ : 1784, 1715,1524, 1333, 1055, 837.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

0.08 (3.6H, singlet);

0.09 (2.4H, singlet);

0.86 (9H, singlet);

1.24 (3H, doublet, J=6 Hz);

1.39 (3H, doublet, J=7 Hz);

1.41 (1.8H, triplet, J=7 Hz);

1.44 (1.2H, doublet, J=7 Hz);

2.93-3.10 (2H, multiplet);

3.38 (0.6H, doublet of doublets, J=3 & 5 Hz);

3.41 (0.4H, doublet of doublets, J=3 & 5 Hz);

3.61 (0.6H, doublet of doublets, J=10 & 7 Hz);

3.85 (0.4H, doublet of quartets, J=10 & 7 Hz);

4.23-4.34 (1.6H, multiplet);

4.42 (0.4H, doublet of doublets, J=3 & 10 Hz);

5.27 (0.4H, doublet, J=14 Hz);

5.32 (0.6H, doublet, J=14 Hz);

5.41 (0.6H, doublet, J=14 Hz);

5.44 (0.4H, doublet, J=14 Hz);

7.63 (1.2H, doublet, J=9 Hz);

7.66 (0.8H, doublet, J=9 Hz);

8.23 (2H, doublet, J=9 Hz).

Mass spectrum (m/z): 479 (M⁺ (C₂₅ H₃₆ N₂ O₇ SSi)-t-Bu).

PREPARATION 50

4-Nitrobenzyl(5R,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-2-ethylsulfinylpenem-3-carboxylate##STR91##

20 ml of a methylene chloride solution containing 1.039 g (1.98 mmol) of4-nitrobenzyl(5R,6S)-6-[1(R)-t-butyldimethylsilyloxyethyl]-2-ethylthiopenem-3-carboxylatewas cooled in an ice bath and 469 mg of m-chloroperbenzoic acid (purity80%) was added carefully over a period of 5 minutes to the cooledsolution. The reaction mixture was stirred for 30 minutes at the sametemperature and then a further 88 mg of m-chloroperbenzoic acid (purity80%) (making a total of 557 mg, 2.58 mmol) were added, and the mixturewas stirred for a further 15 minutes. At the end of this time, thereaction mixture was diluted with methylene chloride and washed with adilute aqueous solution of sodium hydrogencarbonate. The organic layerwas condensed by evaporation under reduced pressure, and the resultingresidue was purified by column chromatography through 50 g of silicagel. Elution with a 4:6 by volume mixture of ethyl acetate and hexaneafforded, in order, the following:

202 mg (yield 19%) of an S-oxide lower polarity as a foam-like solid;

336 mg (31% yield) of a mixture of the S-oxides of lower and higherpolarity in a ratio of 1:3, and

72 mg (7% yield) of an S-oxide of higher polarity as a foam-like solid.

In Examples 29 and 30, all three of the fractions separated by columnchromatography were recombined for use as the starting materials.

Isomer of Lower Polarity

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻ : 1796, 1701,1524, 1323, 1063.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

0.05 (3H, singlet);

0.08 (3H, singlet);

0.84 (9H, singlet);

1.26 (3H, doublet, J=6 Hz);

1.44 (3H, triplet, J=7 Hz);

3.10 (2H, quartet, J=7 Hz);

3.92 (1H, doublet of doublets, J=1 & 3 Hz);

4.28 (1H, doublet of quartets, J=3 & 6 Hz);

5.26 (1H, doublet, J=14 Hz);

5.38 (1H, doublet, J=14 Hz);

5.73 (1H, doublet, J=1 Hz);

7.62 (2H, doublet, J=9 Hz);

8.23 (2H, doublet, J=9 Hz).

Isomer of Higher Polarity

Infrared Absorption Spectrum (liquid film), ν_(max) cm⁻ : 1794, 1702,1524, 1321, 1063.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz) δ ppm:

0.04 (3H, singlet);

0.07 (3H, singlet);

0.82 (9H, singlet);

1.26 (3H, doublet, J=6 Hz);

1.44 (3H, triplet, J=7 Hz);

3.13 (2H, doublet of quartets, J=4 & 8 Hz);

3.90 (1H, doublet of doublets, J=2 & 4 Hz);

4.27 (1H, doublet of quartets, J=4 & 6 Hz);

5.22 (1H, doublet, J=14 Hz);

5.41 (1H, doublet, J=14 Hz);

5.85 (1H, doublet, J=2 Hz);

7.59 (2H, doublet, J=9 Hz);

8.23 (2H, doublet, J=9 Hz).

PREPARATION 51

4-Nitrobenzyl(1R,5S,6S)-2-[(3S,6-S)-5-dimethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-3-pyrrolidinylthio]-1-methyl-6-[1(R)-hydroxyethyl]-1-carbapen-2-em-3-carboxylate ##STR92##

8 mg (0.039 mmol) of citric acid hydrate were added to 2 ml of asolution containing 55 mg of 4-nitrobenzyl(1R,5S,6S)-2-[(3S,5-S)-5-dimethylcarbamoyl-1-(4-nitrobenzyloxycarbonyl)-3-pyrrolidinylthio]-1-methyl-6-[1(R)-trimethylsilyloxyethyl]-1-carbapen-2-em-3-carboxylate (prepared as described in Example 18) in methanol,and the resulting mixture was stirred at room temperature for 35minutes. At the end of this time, the solvent was removed bydistillation under reduced pressure, and the residue was purified bycolumn chromatography through 5 g of silica gel, using a 1:9 by volumemixture of methanol and ethyl acetate as the eluent, to give 42 mg(yield 84%) of the title compound as a vitreous solid.

The physicochemical properties of this compound were in agreement withthose of the compound prepared as described in Example 27.

PREPARATION 52

S-2-Diethylcarbamoylphenyl 2(R)-{2S,3S)-3-[1(R)-(t-butyldimethylsilyloxy)ethyl]-4-oxo-2-azetidinyl}thiopropionate##STR93## 52(a)1-t-Butyldimethylsilyloxy-1-(2-diethylcarbamoyl)-phenylthio-1-propene

1.7 ml (12.2 mmol) of triethylamine were added to a solution of 3.20 g(12.1 mmol) of S-(2-diethylcarbamoyl)phenyl thiopropionate, which isdescribed in Referential Example 12 of Japanese Patent Kokai ApplicationNo. Hei 4-174099, and 3.64 g (24.1 mmol) of t-butyldimethylsilylchloride in a mixture of 12 ml of dimethylformamide and 12 ml oftetrahydrofuran, and the resulting mixture was stirred at roomtemperature for 3 minutes. At the end of this time, the solution wascooled to -78° C., and 12.1 ml of a 1.0M tetrahydrofuran solution oflithium bis(trimethylsilyl)amide were added dropwise over a period of 20minutes. The mixture was then stirred at the same temperature for 30minutes, after which 10 ml of a saturated aqueous solution of sodiumhydrogencarbonate were added. The reaction mixture was then extractedwith hexane, and the extract was washed twice with water, once with a 2Naqueous solution of sodium hydroxide, three times with water and oncewith a saturated aqueous solution of sodium chloride, in that order. Theextract was then dried over anhydrous magnesium sulfate, and the solventwas removed by distillation under reduced pressure. The resultingresidue was again dissolved in hexane, and the solution was mixed with9.0 g of aluminum oxide for chromatography and then stirred for 15minutes. The aluminum oxide was removed from the mixture by filtration,and the aluminum oxide was washed with hexane. The filtrate and thewashings were combined and the solvent was removed by distillation underreduced pressure, to give 4.24 g ofZ(O)-1-t-butyldimethylsilyloxy-1-(2-diethylcarbamoyl)phenylthio-1-propene. Analysis by nuclear magnetic resonancespectroscopy (270 MHz) showed that the ratio of the Z(O)-isomer to theE(O)-isomer in the product was more than 20.

52(b) S-2-Diethylcarbamoylphenyl2(R)-{(2S,3)-3-[1(R)-(t-butyldimethylsilyloxy)ethyl]-4-oxo-2-azetidinyl}thiopropionate

1.49 g (10.9 mmol) of anhydrous zinc chloride were added to a solutionof 4.24 g of Z(O)-1-t-butyldimethylsilyloxy-1-(2-diethylcarbamoyl)phentylthio-1-propene [prepared as described in step (a) above] and 1.57g (5.47 mmol) of(3R,4S)-3-[1(R)-t-butyldimethylsilyloxyethyl]-4-acetoxy-2-azetidinone in55 ml of methylene chloride, and the resulting mixture was heated underreflux for 40 minutes. At the end of this time, the reaction mixture wascooled to room temperature, and the solvent was removed by distillationunder reduced pressure. The residue was dissolved in ethyl acetate, andthe solution was washed three times with water and once with a saturatedaqueous solution of sodium chloride. The mixture was then dried overanhydrous magnesium sulfate, after which the solvent was removed bydistillation under reduced pressure, and the residue was recystallizedfrom about 10 ml of diisopropyl ether, to give 2.08 g (yield 77%) of thetitle compound as crystals, melting at 130.5°-132° C.

Nuclear Magnetic Resonance Spectrum (CDCl₃, 270 MHz), δ ppm:

0.08 (6H, singlet);

0.87 (9H, singlet);

1.03 (4H, triplet, J=7 Hz);

1.21 (3H, doublet, J=6 Hz);

1.25 (3H, triplet, J=7 Hz);

1.29 (3H, doublet, J=7 Hz);

2.96-3.15 (4H, multiplet);

3.20-3.85 (2H, broad);

3.96 (1H, dd, J=2, 4 Hz);

4.19 (1H, quintet, J=6 Hz);

5.90-6.10 (1H, broad singlet);

7.30-7.35 (1H, multiplet);

7.41-7.51 (3H, multiplet).

Mass spectrum (m/z): 492 (M⁺, C₂₅ H₄₀ N₂ O₄ SSi).

We claim:
 1. A compound selected from the group consistingof4-nitrobenzyl-2-(2-diethylcarbamoylphenylthio)-1-methyl-6-(1-trimethylsilyloxyethyl)-1-carbapen-2-em-3-carboxylate,4-nitrobenzyl-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-(1-trimethylsilyloxyethyl)-1-carbapen-2-em-3-carboxylate,4-nitrobenzyl-2-(2-diethylcarbamoylphenylsulfonyl)-1-methyl-6-(1-trimethylsilyloxyethyl)-1-carbapen-2-em-3-carboxylate,4-nitrobenzyl-2-(2-diethylcarbamoylphenylthio)-1-methyl-6-(1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate,4-nitrobenzyl-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-(1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate,4-nitrobenzyl-2-(2-diethylcarbamoylphenylsulfonyl)-1-methyl-6-(1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate,4-nitrobenzyl-2-[2-(1-perhydroazepinylcarbonyl)phenylthio]-1-methyl-6-(1-trimethylsilyloxyethyl)-1-carbapen-2-em-3-carboxylate,4-nitrobenzyl-2-[2-(1-perhydroazepinylcarbonyl)phenylsulfinyl]-1-methyl-6-(1-trimethylsilyloxyethyl)-1-carbapen-2-em-3-carboxylate,4-nitrobenzyl-2-[2-(1-perhydroazepinylcarbonyl)phenylsulfonyl]-1-methyl-6-(1-trimethylsilyloxyethyl)-1-carbapen-2-em-3-carboxylate,4-nitrobenzyl-2-[2-(1-perhydroazepinylcarbonyl)phenylthio]-1-methyl-6-(1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate,4-nitrobenzyl-2-[2-(1-perhydroazepinylcarbonyl)phenylsulfinyl]-1-methyl-6-(1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate and4-nitrobenzyl-2-[2-(1-perhydroazepinylcarbonyl)phenylsulfonyl]-1-methyl-6-(1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate;or apharmaceutically acceptable salt thereof or a pharmaceuticallyacceptable ester thereof.
 2. The compound of claim 1, which is4-nitrobenzyl-2-(2-diethylcarbamoylphenylthio)-1-methyl-6-(1-trimethylsilyloxyethyl)-1-carbapen-2-em-3-carboxylate.
 3. The compound of claim 1, which is4-nitrobenzyl-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-(1-trimethylsilyloxyethyl)-1-carbapen-2-em-3-carboxylate.
 4. The compound of claim 1, which is4-nitrobenzyl-2-(2-diethylcarbamoylphenylsulfonyl)-1-methyl-6-(1-trimethylsilyloxyethyl)-1-carbapen-2-em-3-carboxylate.
 5. The compound of claim 1, which is4-nitrobenzyl-2-(2-diethylcarbamoylphenylthio)-1-methyl-6-(1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate.
 6. The compound of claim 1, which is4-nitrobenzyl-2-(2-diethylcarbamoylphenylsulfinyl)-1-methyl-6-(1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate.
 7. The compound of claim 1, which is4-nitrobenzyl-2-(2-diethylcarbamoylphenylsulfonyl)-1-methyl-6-(1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate.
 8. The compound of claim 1, which is4-nitrobenzyl-2-[2-(1-perhydroazepinylcarbonyl)phenylthio]-1-methyl-6-(1-trimethylsilyloxyethyl)-1-carbapen-2-em-3-carboxylate.9. The compound of claim 1, which is4-nitrobenzyl-2-[2-(1-perhydroazepinylcarbonyl)phenylsulfinyl]-1-methyl-6-(1-trimethylsilyloxyethyl)-1-carbapen-2-em-3-carboxylate.10. The compound of claim 1, which is4-nitrobenzyl-2-[2-(1-perhydroazepinylcarbonyl)phenylsulfonyl]-1-methyl-6-(1-trimethylsilyloxyethyl)-1-carbapen-2-em-3-carboxylate.11. The compound of claim 1, which is4-nitrobenzyl-2-[2-(1-perhydroazepinylcarbonyl)phenylthio]-1-methyl-6-(1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate.
 12. Thecompound of claim 1, which is4-nitrobenzyl-2-[2-(1-perhydroazepinylcarbonyl)phenylsulfinyl]-1-methyl-6-(1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate.
 13. Thecompound of claim 1, which is4-nitrobenzyl-2-[2-(1-perhydroazepinylcarbonyl)phenylsulfonyl]-1-methyl-6-(1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate.